Immunostimulatory RNA/DNA hybrid molecules

ABSTRACT

The present invention provides immunological compositions and methods relating to immunostimulatory intra-strand DNA/RNA hybrid oligonucleotides (HDRs), optimally encoding one or more CpG motif, which may be an unmethylated CpG motif. Administration of these compounds, alone or in the context of one or more target antigens, promotes innate and antigen specific immunities.

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This present application is based upon U.S. provisional application Serial No. 60/209,797, filed Jun. 7, 2000, priority to which is claimed under 35 U.S.C. § 119(e), the entire disclosure of which is incorporated by reference.

FIELD OF THE INVENTION

[0002] The present invention relates to immunostimulatory RNA/DNA hybrid oligonucleotides and their use in enhancing an immune response, or inducing cytokines. The present invention further relates to a novel adjuvanting system comprising DNA, RNA, and/or RNA/DNA hybrid oligonucleotides containing CpG dinucleotides, which may be unmethylated CpG dinucleotides, conjugated to a high molecular weight polysaccharide or other polyvalent carrier.

BACKGROUND

[0003] The use of nucleic acids as immunostimulatory molecules has recently gained acceptance. The immunoreactive properties of nucleic acids are determined by their base composition, modifications, and helical orientation. For example, humoral immune responses to cellular DNAs have been implicated in unusual DNA structures, such as Z-DNA, which can induce significant antibody responses in experimental animals. Double stranded nucleic acids comprising DNA, RNA, and inter-strand DNA:RNA hybrids all have the potential for generating a humoral immune response. Eliat and Anderson, Mol. Immunol. 31:1377 (1994). Indeed, antibodies directed against cellular DNA have long been implicated in the autoimmune condition systemic lupus erythematosus.

[0004] It is also known that DNA sequences containing certain unmethylated CpG sequences, sometimes called “CpG ODNs” (CpG oligodeoxynucleotides), are highly stimulatory of cells in the immune system, and can induce vigorous proliferation and immunoglobulin (Ig) production by B cells. See generally Klinman et al., Vaccine 17:19 (1999); and McCluskie and Davis, J. Immun. 161:4463 (1998) (each of which is incorporated herein by reference in its entirety). Interestingly, these unmethylated CpG dinucleotides are far more frequent in the genomes of bacteria and viruses than vertebrates and may contribute to vertebrates' innate immune responses to bacteria and viruses. Klinman et al., Proc. Natl. Acad. Sci. USA 93:2879 (1996); Yi et al. J. Immun. 157: 5394 (1996); Hua Liang et al., J. Clin. Invest. 98:1119 (1996); Krieg et al., Nature 374: 546 (1995), each of which is incorporated herein by reference in its entirety.

[0005] Since the interest in CpG DNA began, studies have focused on the possible mechanism of action. In mice, CpG DNA induces proliferation in almost all (>95%) B cells. These oligonucleotides stimulate immunoglobin (Ig) secretion and may act by increasing the secretion of IL-6from B cells. This B cell activation by CpG DNA is T cell independent and antigen non-specific. In addition to its direct effects on B cells, CpG DNA also directly activates monocytes, macrophages, and dendritic cells to secrete a variety of cytokines, including IL-6, IL-12, GMC-CSF, TNF-α, CSF, and interferons. These cytokines stimulate natural killer (NK) cells to secrete γ-interferon (IFN-γ) and have increased lytic activity. Examples of applications covering these aspects can be found in International Patent Applications WO 95/26204, WO 96/02555, WO 98/11211, WO 98/18810, WO 98/37919, WO 98/40100, WO 98/52581, and PCT/US98/047703; and U.S. Pat. No. 5,663,153, each of which is incorporated herein by reference in its entirety.

[0006] In light of the above observations, oligonucleotides, particularly those containing various formulations of CpG motifs, have frequently been suggested as vaccine adjuvants, or stimulants of global immune responses. Reviewed in Immunobiology of Bacterial CpG-DNA (Springer, 2000, H. Wagner ed.) (each of which is incorporated herein by reference in its entirety.) In practice, such oligonucleotides are somewhat effective but have been constructed entirely of DNA or DNA analogs. See, for example, Kreig et al., in Immunobiology of Bacterial CpG-DNA, cited above.

[0007] In addition to CpG-containing DNAs, a number of other polynucleotides have been evaluated as biological response modifiers. Perhaps the best example is poly (I,C) which is a potent inducer of interferon (IFN) production as well as a macrophage activator and inducer of NK activity. Its potent in vitro antitumor activity led to several clinical trials using poly (I,C) complexed with poly-L-lysine and carboxymethylcellulose (to reduce degradation by RNAse). (Talmadge, et al., Cancer res. 45:1058 (1985); Wiltrout, et a., J. Biol. Resp. Mod. 4:512 (1985) Krown, Sem. Oncol. 13:207 (1986); and Ewel, et al., Canc. Res. 52:3005 (1992)). In contrast to the CpG-based oligonucleotides, the immunostimulatory effects of poly (I,C) appear to be specific for the ribose sugar-based forms of these bases, since deoxyribose-based ply (I,C) was ineffective. Nevertheless, toxic side effects have thus far prevented poly (I,C) from becoming a useful therapeutic agent. In contrast, CpG based compositions may provide useful anti-cancer therapies, adjuvants, and modifiers of cytokine secretion profiles.

[0008] Thus, there exists a need for immunostimulatory oligonucleotides that optimally induce both global and specific immune responses, and that might be directed in their ability to induce T-cell dependent or B-cell dependent responses and/or specifically Th1 or Th2 responses. In addition, there is a need for methods utilizing these oligonucleotides as vaccine adjuvants and in the treatment of disease.

SUMMARY OF THE INVENTION

[0009] The inventors have discovered that oligonucleotides comprising intra-strand hybrids of RNA and DNA, optionally encoding one or more CpG motifs, address these needs by providing highly efficacious global and antigen-specific immune stimulation. These and other advantages of the present invention, as well as additional inventive features, will be apparent from the description of the invention provided herein.

DETAILED DESCRIPTION OF THE INVENTION

[0010] As discussed above, oligonucleotide sequences based solely on DNA and DNA derivatives display immunostimulatory activities. In contrast, the immunogenic and immunotherapeutic compositions and methods of the present invention relate to novel hybrid DNA/RNA oligonucleotides (HDRs). Surprisingly, these hybrid oligonucleotide sequences display different, and in some aspects, superior, immunostimulory characteristics than those based solely on DNA. This is particularly surprising in view of the inoperability of RNA-based molecules. Indeed, there is not a single report of a successful immune modulator based on RNA.

[0011] The mixed-backbone of ribose and deoxyribose nucleotides in the instant HDRs provides an efficacious alternative to the known immunostimulatory oligonucleotide compositions. Moreover, when compared to standard CpG polynucleotide formulations, the HDRs of the invention demonstrate increased activities in a variety of T cell-dependent applications, elicit more defined cytokine production profiles from B cells and other cell types, and are effective stimulants of T cell-independent immunity.

[0012] Without limitation to any particular theory of the invention, it is presently believed that the HDRs of the invention directly or indirectly influence cells of the immune system by altering the quantity or amount of stimulatory and inhibitory cytokines produced by cells of the immune system. These HDR-sensitive cells include macrophages, T cells, NK cells, and dendritic cells involved in both acquired and innate immunities (discussed at length in Ivan Roit, Essential Immunology (8^(th) Ed. 1994) (incorporated herein by reference in its entirety). In addition, for the purpose of this invention, global immunity refers to the overall sensitivity of a patient's immune response and its ability to mount effective defenses against any foreign entity, including inappropriately presented endogenous antigens.

[0013] Acquired immunity comprises a host's response to antigenic challenge by both foreign (e.g. allergens, pathogens, transplanted tissues) and self-derived (e.g. tumor antigens, autoantigens) antigens, and is preferably associated with a memory response. Acquired immunity encompasses both cell-mediated (e.g. cytotoxic activity) and humoral immunity (resulting in the production of antibodies) and generally depends on regulation by T cells and NK cells.

[0014] T cells play a central role in many aspects of acquired immunity, carrying out a variety of regulatory and defensive functions. When some T cells encounter an infected or cancerous cell, they recognize it as foreign and respond by acting as killer cells, killing the host's own cells as part of the cell-mediated immune response. Other T cells, designated helper T cells, respond to perceived foreign antigens by stimulating B cells to produce antibodies, or by suppressing certain aspects of a humoral or cellular immune response.

[0015] T helper cells (Th) orchestrate much of the immune response via the production of cytokines. Although generally identifiable as bearing the CD4 cell surface marker, these cells are functionally divided into Th1 or Th2 subpopulations according to the profile of cytokines they produce and their effect on other cells of the immune system.

[0016] The Th1 cells detect invading pathogens or cancerous host cells through a recognition system referred to as the T cell antigen receptor. Termed cellular immunity, Th1-related processes generally involve the activation of non-B cells and are frequently characterized by the production of IFN-γ. Nevertheless, although the Th1 system is primarily independent from the production of humoral antibodies, Th1 cytokines do promote immunoglobulin class switching to the IgG_(2a) isotype.

[0017] Upon detection of a foreign antigen, most mature Th1 cells direct the release of IL-2, IL-3, IFN-γ, TNF-β, GM-CSF, high levels of TNF-α, MIP-1α, MIP-1β, and RANTES. These cytokines promote delayed-type hypersensitivity and general cell-mediated immunity. IL-2, for instance, is a T cell growth factor that promotes the production of a clone of additional T cells sensitive to the particular antigen that was initially detected. The sensitized T cells attach to and attack cells or pathogens containing the antigen.

[0018] In contrast, mature Th2 cells tend to promote the secretion of IL-3, IL4, IL-5, IL-6, IL-9, IL-10, IL-13, GM-CSF, and low levels of TNF-α. In addition, the Th2 response promotes humoral immunity by activating B cells, stimulating antibody production and secretion, and inducing class switching to IgA, IgG, and IgE isotypes.

[0019] In nature, the stimulation of B cells leading to a humoral or systemic immune response depends on the ability of the B cells to recognize specific antigens. B cells recognize antigens via specific receptors on their cell surface called immunoglobulins or antibodies. When an antigen attaches to the receptor site of a B cell, the B cell is stimulated to divide to form daughter cells. In the case of a T-cell independent antigen, such as a bacterial polysaccharide, the B cell activation results in a low level response, characterized by little, if any class switching or memory response. In contrast, T-cell dependent antigens stimulate receptors on both B cells and Th2 cells, resulting in a vigorous and complex humoral immune response. Specifically, cytokines such as IL-6, produced by stimulated Th2 cells, cause the B cells to mature and produce antibodies. Maturation includes class-switching from the primitive IgM isotype, the production of memory cells, and the selection of high affinity antigen binding specificities.

[0020] The Th1 and Th2-type cytokines also affect the Th populations themselves. For example, IL-12 and IFN-γ up regulate Th1 responses but down regulate Th2 cells. IL-12 itself promotes IFN-γ production, providing a positive feed back for IL-12 production by Th1 cells. In addition, NK cells also regulate Th1 and Th2 immunity by secreting IFN-γ. The signal for NK cells to secrete IFN-γ may be precipitated by cytokines released from antigen presenting cells in response to antigen but may also be directly or indirectly precipitated by the addition of the HDRs of the invention.

[0021] Nevertheless, irrespective of the mechanism, the HDRs of the invention can stimulate the production of cytokines characteristic of Th1 regulation, Th2 T regulation, or both—indicative of their efficacy in stimulating both humoral and cellular immunity.

[0022] In addition, induction of one type of immune response may allow for immune regulation because up regulation of one type of immune response may down regulate the other type of immune response. This immune regulation allows for customizing or tailoring of the type of immune response when administering the immunogenic compositions of the invention.

[0023] Moreover, given the wealth of knowledge in the art regarding the use of cytokines to favor (or reduce) particular facets of an immune response, the HDRs of the invention may be administered in conjunction with one or more cytokines. Thus, one or more cytokines or active portions of cytokines may be administered directly, as soluble factors, conjugates, or fusion proteins with antigen or other cytokines, or indirectly, as nucleic acids encoding one or more cytokine activities, to a patient in need of immune stimulation. For example, the compositions and methods disclosed in U.S. Pat. No. 5,874,085 to Mond and Snapper (incorporated herein by reference in its entirety) may be administered with the HDRs of the invention not only to promote a Th2 response, but also to direct isotype switching to predominantly IgA antibodies.

[0024] Similarly, the humoral arm of an HDR-mediated response may comprise a primarily IgG, response if the HDR is administered in conjunction with antigen, GM-CSF and IL-2, as taught in copending U.S. application Ser. No. 08/568,343 (incorporated herein by reference in its entirety). Moreover, the HDRs of the invention generally promote class switching to isotypes other than the IgE isotype. Consequently, the administration of an HDR with an allergen may ameliorate or prevent an allergic response. The allergen may be administered in association with an HDR of the invention or may be present in the environment of the organism to which an HDR is being administered.

[0025] In addition to the above methods for shaping and enhancing acquired immunities, the HDRs of the invention may also promote an increase in the effectiveness of innate immunity. As used herein, innate immunity is any effect on the immune system which is not intrinsically dependent on prior contact with antigen. Most broadly, this encompasses priming the acquired immunity system in the absence of antigen, for example, by increasing the number of naive or quiescent B, T, NK, or antigen presenting cells or, by increasing their sensitivity to subsequent stimulation.

[0026] Innate immunity further comprises that arm of the immune system which is not directly dependent on T or B lymphocytes. Macrophages, neutrophils and monocytes are important effector cells for innate immunity. Macrophages, for example, play an important role in the destruction of solid tumors, in part, through the production of reactive oxygen intermediates and the cytokine TNF. The macrophage's ability to destroy cells bearing foreign antigens is enhanced by other cytokines that attract or stimulate this cell type. NK cells, for example, may provide an important link between the acquired and innate responses by providing cytokines which attract or stimulate macrophages to destroy cells bearing foreign antigens. By analogy to the effects of CpG-containing ODNs, HDRs may increase the sensitivity of NK cells to IL-12, resulting in an increased release of cytokines such as IFN-γ from the NK population. Alternatively, or in addition, HDRs may initially act on antigen presenting cells (primarily macrophages and dendritic cells), which release cytokines that act on the NK cells. Nevertheless, irrespective of the underlying mechanisms, the administration of the HDRs of the invention to a host can promote innate immunity defenses against both pathogenic invasion and cancerous cells.

[0027] Hybrid DNA/RNA Oligonucleotides

[0028] The present invention provides synthetic HDR molecules of at least about 9 nucleotides in length, but which may be about 10 to 20, 20 to 50, 50 to 100 or more nucleotides in length, including any value subsumed within those ranges. For facilitating uptake into cells, less than 40 nucleotides may be advantageous. Each of the immunostimulatory polynucleotides comprises both RNA and DNA bases, which may include modified polynucleotides and nucleotide analogs. The HDRs may be single-stranded, but also encompass double-stranded, partially double-stranded, and self-complementary hair-pin structures.

[0029] In one embodiment, the HDR comprises a 5′ DNA portion and a 3′ RNA portion; in another embodiment the position of the two portions is reversed. A single HDR may contain multiple DNA and/or RNA portions. In one embodiment, a DNA portion is flanked by RNA portions. Each DNA portion comprises at least 1 nucleotide, but may comprise about 2 to 5, 5 to 10, 10 to 20, 20 to 50 or more nucleotides having a deoxyribose-phosphate backbone, or modification thereof, including any value subsumed within the recited ranges.

[0030] Each RNA portion of the HDR comprises at least 1 nucleotide, but may comprise about 2 to 6, 6 to 10, 10 to 20, 20 to 50 or more nucleotides having a ribose-phosphate backbone, or modification thereof, including any value subsumed within the recited ranges. The RNA portion may be of any base sequence (including a base sequence comprising all or part of a CpG sequence), for example, a run of purine bases. The bases may be of essentially uniform composition, e.g., polyadenine (poly A), polyuracil (poly U), polyguanine (poly G), polycytosine (poly C), and poly inosine or polythymidine (if these bases are linked to a ribose sugar). Complementary runs of nucleotides, for example, poly A and poly U, or poly G and poly C, are preferred where a double-stranded hybrid is contemplated.

[0031] Irrespective of the overall length of an HDR, the optimal ratio of RNA to DNA may be determined empirically. Although about 5, 10, 15, 20, 25, 50, or even more than 75% DNA is acceptable, it is presently believed that in some embodiments a terminal RNA portion may be substantially larger than the DNA portion without adversely affecting the efficacy of the invention. In other embodiments a terminal RNA portion may be substantially smaller than the DNA portion.

[0032] Although optimal sequences for a DNA portion may be determined empirically, at least one portion of an HDR may contain at least one CpG dinucleotide, which may be a CpG sequence, and which may comprise DNA. A “CpG dinucleotide” refers to a nucleic acid sequence having a cytosine followed by a guanine (in 5′ to 3′ orientation) and linked by a phosphate bond. In one embodiment, the pyrimidine ring of the cytosine is unmethylated. Nevertheless, CpG motifs having a methylated cytosine can be effective immunostimulators under certain conditions, (Goeckeritz et al., Internat. Immunol. 11:1693 (1999) (incorporated herein by reference in its entirety)), and thus, CpG motifs as used herein may, but need not necessarily, have an unmethylated cytosine. In further embodiments, HDRs of the invention may comprise multiple CpG motifs which may or may not be separated by RNA nucleotides.

[0033] A “CpG sequence” or “CpG motif”,as used herein, refers to CpG dinucleotides, which may be associated with additional DNA sequence or, for the purposes of this invention, RNA sequence, which contributes to immunostimulatory effects. CpG sequences can be determined empirically according to well known techniques in the art, and may be determined or designed according to various canonical formulae, such as those described in U.S. Pat. Nos. 6,194,388, 6,008,200 and 5,856,462, each of which is incorporated herein by reference in its entirety. In one embodiment of the invention, the CpG dinucleotide comprises DNA, but some or all of the remaining bases of the CpG sequence are RNA. In an alternative embodiment, one or both of the CpG dinucleotides comprise RNA. In another embodiment, the CpG sequence is a palindrome. In yet another embodiment, the CpG sequence comprises DNA and forms a palindrome with all or a portion of an RNA portion of the HDR. In one embodiment, the HDR contains a core DNA hexamer having a CpG dinucleotide. In a presently preferred embodiment the CpG dinucleotide is centered in a core DNA hexamer. Representatives of such hexamers include, but are not limited to, GACGTT, TTCGTA, TTCGAG, AGCGTT, CTCGAG, TTCGTT, AGCGTT, MCGTT, AGCGCT, and GTCGGT. In one embodiment, a core DNA hexamer is flanked by RNA. In another embodiment the core DNA hexamer is flanked by between 1 and 5 DNA nucleotides on either or both sides. These flanking DNA sequences may be flanked by RNA. In another embodiment, flanking DNA sequences on either side of the core hexamer are themselves palindromic.

[0034] In one embodiment, RNA is added to a pre-existing DNA sequence by enzymatic templated or non-templated polymerization. The added RNA portion may be of any length. Resulting RDRs may be of variable length. In one embodiment, RNA is added to a pre-existing CpG-containing oligonucleotide by non-template directed enzymatic synthesis. The added RNA may be a homopolymer, such as poly A, poly U, or poly I.

[0035] HDRs preferably contain one or more CpG dinucleotides which may occur in the context of canonical CpG sequences or motifs. The HDRs of the invention may contain or overlap with a base sequence similar to DNA-based CpG-containing polynucleotides (ODNs) known in the art. Consequently, the hybrid molecules of the invention are useful for the same range of applications as has been suggested for CpG polynucleotides composed entirely of a single sugar backbone (generally deoxyribose). These suggested uses are reviewed in Immunobiology of Bacterial CpG-DNA (Springer, 2000, H. Wagner ed.), which is incorporated herein by reference in its entirety. According to formulae for CpG motifs known in the art, the base sequence of a CpG motif may comprise one or more CpG sequences represented by the formula 5′ N₁N₂MT-CpG-AKN₃N₄ 3′, wherein M is adenine or cytosine; K is guanine or thymidine; and N₁, N₂, N₃, and N₄ are any nucleotides, with the proviso that K is guanine when M is cytosine, and K is thymidine when M is adenine. Thus, an HDR may include a sequence represented by the formula 5′ N₁N₂CT-CpG-AGN₃N₄ 3′ or the formula 5′ N₁N₂AT-CpG-ATN₃N₄3′.

[0036] In other embodiments the DNA portion consists of or overlaps with one or more sets of nucleotides of the formula: 5′ N₁X₁CGX₂N₂ 3′, as described in WO 98/37919 (incorporated herein by reference in its entirety). In these embodiments, at least one nucleotide separates consecutive CpGs; where X₁ is adenine, guanine, or thymidine; X2 is cytosine or thymine; N can be absent, can be a single nucleotide or can be a sequence of nucleotides, with the proviso that N₁+N₂ is from 0-26 bases. In this embodiment, it is preferred that N₁ and N₂ do not contain a CCGG quadramer or more than one CGG trimer. The DNAportion is preferably between 8-30 bases, but may be as little as 2-4 bases, preferably including a CpG dinucleotide. Similarly, the DNA portion may consist of or overlap with one or more sets of nucleotides of the formula: 5′ N₁X₁X₂CGX₃X₄N₂ 3′, wherein X₁X₂ is selected from the group consisting of GpT, GpG, GpA, ApT, and ApA, and X₃X₄ is TpT or CpT.

[0037] A DNA portion comprising the core hexamer sequence CTCGAG, or N_(x)CTCGAGN_(x), where N_(x) is one or more DNA nucleotides, will tend to promote a humoral immune response, whereas a DNA portion comprising the CpG sequence ATCGAT or N_(x)ATCGATN_(x), where N_(x) is one or more DNA nucleotides, will tend to promote a cell-mediated immune response. HDRs containing CTCGAG or ATCGAT hexamers comprising RNA or a combination of RNA and DNA may also tend to promote humoral and cell-mediated immune responses, respectively.

[0038] Additional factors which should be considered when designing an HDR include the species for which the HDR is to be used. For example, Verthelyi et al., J. of Immunology 166: 2372-77 (2001), (which is incorporated herein by reference in its entirety), teaches that CpG sequences of the formula M₁M₂CGN₁N₂, where M₁ and M₂ are A or G and N₁ and N₂ are T or C appear to be optimal in mice but function poorly in humans. CpG sequences that work well in humans include those of the formula M₁N₁CGM₂N₂, where M₁ and M₂ are A or G and N₁ and N₂ are T or C. These guidlines may also apply to HDRs designed according to the above formula, that is, consisting or comprising the same, or substantially the same base sequence, but having one or more deoxyribose moieties substituted with ribose.

[0039] It is also possible to select for ODN sequences which exhibit immunostimulatory specificity. Verthelyi et al. used standard techniques in the art to identify two classes of ODN, designated “D” and “K”. D-class ODNs preferentially stimulate NK cells to secrete IFN-γ, while K-class ODNs preferentially stimulate cell proliferation, activation of monocytes and B cells to secrete IL-6, and production of IgM by B cells. A similar approach can be applied to the HDRs of the invention to identify HDRs which elicit specific immunostimulatory responses.

[0040] In one non-limiting example, a known ODN sequence is modified to replace a portion of the deoxyribose backbone with ribose. In another embodiment, one or more ribonucletides are added to the 3′ or 5′ end of the known ODN sequence. Additional embodiments are, of course, evident from the further teachings of this specification.

[0041] Modifications and Analogs

[0042] The DNA/RNA hybrid polynucleotides of the invention may be synthesized de novo by any techniques known in the art, for example those described in U.S. Pat. No. 5,935,527, (incorporated herein by reference in its entirety), preferably, with any suitable modification which can render the HDR resistant to in vivo degradation resulting from, e.g., exo or endonuclease digestion. For example, the phosphate backbone may be modified by phosphorothioate backbone modification wherein one of the non-bridging oxygens is replaced with sulfur, as set forth in International Patent Application WO 95/26204; U.S. Pat. No. 5,003,097; Stein et al., Nuc. Acids Res. 16(8):3209-21 (1988); Stein, et al., Anal. Biochem. 188:11 (1990); Lyer et al., J. Am. Chem. Soc. 112:1253-54 (1990); and Metelev and Agrawal, Anal. Biochem. 200:342-346 (1992), each of which is incorporated herein by reference in its entirety. Phosphorothioate modifications can occur anywhere in the polynucleotide, preferably at either or both termini, e.g., at least the last two or three 3′ and/or 5′ nucleotides can be liked with phosphorothioate bonds. In one embodiment, all of the RNA bases are linked by phosphorothioate bonds and, alternatively, all nucleotides of the HDR may be linked with phosphorothioate bonds. The HDRs may also be modified to contain a secondary structure (e.g., stem loop structure) such that it is resistant to degradation.

[0043] Another modification that renders the RNA and DNA moieties of the HDR less susceptible to degradation is the inclusion of nontraditional bases such as inosine, as well as acetyl-, thio- and similarly modified forms of adenine, cytidine, guanine, thymine, and uridine. Other modified nucleotides include nonionic analogs, such as alkyl or aryl phosphonates (i.e., the charged phosphonate oxygen is replaced with an alkyl or aryl group, as set forth in U.S. Pat. No. 4,469,863, which is incorporated herein by reference in its entirety), phosphodiesters and alkylphosphotriesters (i.e., the charged oxygen atom is alkylated, as set forth in U.S. Pat. No. 5,023,243 and European Patent No. WO 092 574, each of which is incorporated herein by reference in its entirety). Methods for making other DNA backbone modifications and substitutions are described in Uhlmann and Peyman, Chem. Rev. 90:544 (1990); and Goodchild, Bioconjugate Chem. 1:165 (1990), each of which is incorporated herein by reference in its entirety.

[0044] HDRs may be ionically or covalently conjugated to appropriate molecules using techniques which are well known in the art, for example, those described by S. S. Wong in Chemistry of Protein Conjugation and Cross-Linking, CRC Press (1991) and Greg T. Hermanson in Bioconjugate Techniques, Academic Press (1996), each of which is incorporated herein by reference in its entirety. Appropriate molecules include high molecular weight molecules such as polysaccharides, poly-L-lysine, carboxymethylcellulose, polyethylene glycol, or polypropylene glycol, haptenic groups, peptides, and antigens. HDRs containing a diol, such as tetraethyleneglycol or hexaethyleneglycol, at either or both termini, may be more resistant to degradation. A variety of coupling or cross-linking agents can be used, e.g., protein A, carbodiimide, and N-succinimidyl-3-(2-pyridyldithio) propionate (SPDP).

[0045] Pharmaceutical Compositions

[0046] The present invention further provides immunostimulatory compositions comprising one or more HDR sequences alone, or admixed with one or more antigens, moieties, or carriers. The immunostimulatory compositions of the invention may be considered pharmaceutical compositions or, more specifically, immunological compositions in that they elicit a biological effect on the immune system.

[0047] An immunostimulatory composition comprising at least one HDR and at least one antigen may be considered immunogenic. As used herein, an antigen is other than an HDR and comprises the following combinations of moieties: 1) at least one T cell epitope, or 2) at least one B cell epitope or, 3) at least one T cell epitope and at least one B cell epitope. Preferably, an immunogenic composition is capable of stimulating an antigen-specific cellular or humoral immune response, preferably characterized by immunologic memory.

[0048] In one embodiment, the antigen comprises at least one polynucleotide sequence operationally encoding one or more antigenic polypeptides. Used in this context, the word “comprises” intends that at least one antigenic polypeptide is provided by the transcription and/or translation apparatus of a host cell acting upon an exogenous polynucleotide that encodes at least one antigenic polypeptide, as described, for example in U.S. Pat. Nos. 6,194,389 and 6,214,808.

[0049] A vaccine preferably comprises an immunostimulatory composition of the invention associated with, i.e., suspended, dissolved, admixed, adhered, or embedded in, a pharmaceutically acceptable carrier. Moreover, as used herein, a vaccine refers to an immunostimulatory composition comprising one or more HDR sequences for administration to an organism for any prophylactic, ameliorative, palliative, or therapeutic purpose, irrespective of the presence or absence of an antigenic epitope. By way of example, one or more HDRs of the invention in the presence of antigen may comprise a vaccine for the stimulation of specific humoral and/or cellular immunity. Nevertheless, one or more HDRs in the absence of antigen may comprise a vaccine for the stimulation of global or innate immunity.

[0050] As used herein, a pharmaceutical composition or vaccine comprises at least one immunological composition, which may be dissolved, suspended, or otherwise associated with a pharmaceutically acceptable carrier or vehicle. Any pharmaceutically acceptable carrier can be employed for administration of the composition. Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, 18th Edition (A. Gennaro, ed., 1990) Mack Pub., Easton, Pa., which is incorporated herein by reference in its entirety. Carriers can be sterile liquids, such as water, polyethylene glycol, dimethyl sulfoxide (DMSO), oils, including petroleum oil, animal oil, vegetable oil, peanut oil, soybean oil, mineral oil, sesame oil, and the like. Carriers can be in the form of mists, sprays, powders, waxes, creams, suppositories, implants, salves, ointments, patches, poultices, films, or cosmetic preparations.

[0051] Proper formulation of the pharmaceutical composition or vaccine is dependent on the route of administration chosen. For example, with intravenous administration by bolus injection or continuous infusion, the compositions are preferably water soluble, and saline is a preferred carrier. For transcutaneous, intranasal, oral, gastric, intravaginal, intrarectal, or other transmucosal administration, penetrants appropriate to the barrier to be permeated may be included in the formulation and are known in the art. For oral administration, the active ingredient may be combined with carriers suitable for inclusion into tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions, and the like. Time-sensitive delivery systems are also applicable for the administration of the compositions of the invention. Representative systems include polymer base systems such as poly(lactide-glycoside), copolyoxalates, polycaprolactones, polyesteramides, polyorthoesters, polyhydroxybutyric acid and polyanhydrides. These and like polymers may be formulated into microcapsules according to methods known in the art, for example, as taught in U.S. Pat. No. 5,075,109, which is incorporated herein by reference in its entirety. Alternative delivery systems appropriate for the administration of the disclosed immunostimulatory compounds of the invention include those disclosed in U.S. Pat. Nos. 6,194,389, 6,024,983 5,817,637, 6,228,621, 5,804,212, 5,709879, 5,703,055, 5,643,605, 5,643,574, 5,580,563, 5,239,660, 5,204,253, 4,748,043, 4,667,014, 4,452,775, 3,854,480, and 3,832,252 (each of which is incorporated herein by reference in its entirety).

[0052] Aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injectable or aerosol solutions. For administration by aerosol, as by pressurized spray or nebulizer, suitable propellants may be added as understood by those familiar with the art. The immunological composition may also be formulated with solubilizing agents; emulsifiers; stabilizers; dispersants; flavorants; adjuvants; carriers; anesthetics such as bubivaccaine, lidocaine, xylocaine, and the like; antibiotics; and known or suspected anti-viral, anti-fungal, anti-parasitic, or anti-tumor compounds.

[0053] Treatment and Administration

[0054] The present invention encompasses methods of treating a patient in need of immune stimulation by administering a composition comprising one or more of the HDR sequences of the invention, in the presence or absence of an antigen. As used herein, treatment encompasses corrective, restorative, ameliorative, and preventive methods relating to any disease, condition, abnormality, or symptom. Treatment further encompasses the elicitation or suppression of an immune response in an experimental animal or ex vivo.

[0055] Thus, treatment comprises administering an immunostimulatory amount of any of the immunostimulatory compositions of the invention by any method familiar to those of ordinary skill in the art, commonly including oral and intranasal routes, and intravenous, intramuscular, and subcutaneous injections, but also encompassing, intraperitoneal, intracorporeal, intra-articular, intraventricular, intrathecal, topical, tonsillar, mucosal, transdermal, intravaginal, administration and by gavage.

[0056] As is recognized by the skilled practitioner, choosing an appropriate administration method may contribute to the efficacy of a treatment, and local administration may be preferred for some applications. Acceptable routes of local administration include subcutaneous, intradermal, intraperitoneal, intravitreal, inhalation or lavage, oral, intranasal, and directed injection into a predetermined tissue, organ, joint, tumor, or cell mass. For example, mucosal application or injection into mucosal lymph nodes or Peyer's patches may promote a humoral immune response with substantial IgA class switching. Alternatively, targeted injection into a lesion, focus, or affected body site may be applicable for the treatment of solid tumors, localized infections, or other situs requiring immune stimulation.

[0057] Alternatively, cells of the immune system (e.g., T cells, B cells, NK cells, or oligodendrocytes) may be removed from a host and treated in vitro. The treated cells may be further cultured or reintroduced to a patient (or to a heterologous host) to provide immune stimulation to the patient or host. For example, bone marrow cells may be aspirated from a patient and treated with an HDR to stimulate global or specific immunity. High-dose radiation, or comparable treatments, may then be used to destroy the remaining immune cells in the patient. Upon re-implantation, the autologous HDR-stimulated cells will restore normal immune function in the patient. Alternatively, NK and/or T cells isolated from a patient suffering from cancer may be exposed in vitro to one or more HDRs in the presence of antigens specific to the patient's cancer. Upon re-implantation into the patient, the HDR-stimulated cells will deploy a vigorous cellular immune response against the cancerous cells.

[0058] Immunostimulatory Amount

[0059] An immunostimulatory (efficacious) amount refers to that amount of vaccine that is able to stimulate an immune response in a patient which is sufficient to prevent, ameliorate, or otherwise treat a pathogenic challenge, allergy, or immunologic abnormality or condition. If co-administered with an antigen of interest, an immunostimulatory amount is that amount which provides a measurable increase in a humoral or cellular immune response to at least one epitope of the antigen as compared to the response obtained if the antigen is administered in the absence of the HDR. Thus, for example, an immunostimulatory amount refers to that amount of an HDR-containing composition that is able to promote the production of antibodies directed against an antigenic epitope of interest or stimulate a detectable protective effect against a pathogenic or allergenic challenge.

[0060] Alternatively, if administered to a patient in the presence or absence of antigen, an immunostimulatory amount comprises that amount which stimulates innate immunity. Innate immunity, as noted above, is the ability of an immune system to respond to primary and secondary antigenic challenge and includes the ability to monitor and combat non-malignant tumors, malignant cells, and primary challenge by pathogenic viruses or organisms. Thus, the stimulation of innate immunity encompasses the stimulation of any humoral or cellular immune response, but it is not necessarily related to the co-administration of an antigen. Thus, in this context an immunostimulatory amount is that which is sufficient to prevent or decrease tumor expansion, metastasis, or the morbidity or mortality associated with a pathogenic infection.

[0061] Treatment with an immunostimulatory amount of an HDR-containing composition of the invention comprises effecting any directly, indirectly, or statistically observable or measurable increase or other desired change in the immune response in a host, specifically including an ex vivo tissue culture host, comprising at least one cell of the immune system or cell line derived therefrom. Host cells may be derived from human or animal peripheral blood, lymph nodes or the like. Preferred tissue culture hosts include freshly isolated T cells, B cells, macrophages, oligodendrocytes, NK cells, and monocytes, each of which may be isolated or purified using standard techniques. Observable or measurable responses include, B or T cell proliferation or activation; increased antibody secretion; isotype switching; increased cytokine release, particularly the increased release of one or more of IL-1, IL-2, IL-3, IL4, IL-5, IL-6, IL-9, IL-10, IL-12, IL-13, GM-CSF, IFN-γ, TNF-α, TNF-β, GM-CSF, MIP-1α, MIP-1β, or RANTES; increased antibody titer or avidity against a specific antigen; reduced morbidity or mortality rates associated with a pathogenic infection; promoting, inducing, maintaining, or reinforcing viral latency; suppressing or otherwise ameliorating the growth, metastasis, or effects of malignant and non-malignant tumors; and providing prophylactic protection from a disease or the effects of a disease.

[0062] Where the suppression of an immunological response is desired, for example, in the treatment of autoimmune disease or allergy, an effective amount also encompasses that amount sufficient to effect a measurable or observable decrease in a response associated with the condition or pathology to be treated.

[0063] Immunization Schedule

[0064] The amount of an HDR-containing composition to be administered and the frequency of administration can be determined empirically and will take into consideration the age and size of the patient being treated, and the condition or disease to be addressed. An appropriate dose is within the range of 0.01 to 1000 μg, 0.1 to 100 μg, 1 to 50 μg, of HDR per inoculum in a mouse, including any value subsumed within the recited ranges. The amount may be considerably higher in human patients and other larger animals, particularly where a global stimulation of innate immunity is desired. The composition of the invention may be administered continuously by transcutaneous diffusion, intravenous drip, implantable pump, or other suitable delivery system known in the art, preferably in the absence of a target antigen. Where the HDR is administered in the context of a target antigen, an acceptable amount of the target is 0.01 μg to 100 μg per inoculum, but higher and lower amounts may also be indicated. Secondary booster immunizations may be given at intervals ranging from one week to many months later.

[0065] HDR Adjuvants and Vaccines

[0066] In a preferred embodiment, the HDRs of the invention comprise an adjuvant, defined herein as a composition that promotes or enhances an immune response to a target antigen. Although an adjuvant is not desirably immunogenic, many adjuvants do elicit antibodies. Cholera toxin, for example, elicits a vigorous humoral immune response but, if administered as an adjuvant in conjunction with a target antigen, it also promotes an increased antibody response to epitopes of the target. In contrast, a target antigen is an antigen against which a cellular and/or humoral immune response is desired.

[0067] Thus, the hallmark of an adjuvant is the ability to promote an increased humoral or cellular response against at least one epitope not present in the adjuvanting molecule. In one embodiment, this epitope may be expressed on a target antigen administered as a vaccine. In another embodiment, where an HDR-containing composition is administered to boost innate immunity, the target antigen may comprise an epitope of an infectious agent or tumor cell which was not deliberately administered to the patient. In the latter embodiment, as in other embodiments described herein, it is not required that the target be specifically known or identified.

[0068] The adjuvants of the present invention all comprise at least one HDR sequence. In one embodiment, the adjuvant is administered in conjunction with at least one target antigen, however, because HDRs globally stimulate the immune response, the adjuvant may be administered within 48 hours, within 24 hours, or within 12 hours of contacting the specific antigen. To maximize the efficacy of treatment, the adjuvant may be administered before or contemporaneously with the target antigen. Thus, the HDR may be co-administered with an antigen, and may be directly or indirectly associated, complexed, or covalently bound to one or more antigenic substance. Methods for covalent conjugation are known in the art and include those described in S.S. Wong, Chemistry of Protein Conjugation and Cross-Linking, CRC Press (1991) and Greg T. Hermanson in Bioconjugate Techniques, Academic Press (1996), each of which is incorporated herein by reference in its entirety.

[0069] When the HDR is used as an adjuvant for a target antigen, the antigen of interest may be co-administered with traditional adjuvants (such as alum, Freund's complete and incomplete adjuvants, LPS, cholera toxins, liposomes, BCG, DETOX, Titermax Gold, and the like), as is commonly practiced in the art.

[0070] Thus, an adjuvant comprising one or more HDRs can be used to improve the efficacy of any suitable vaccine containing a target antigen. Examples of suitable vaccines can be found in the 54^(th) edition of the Physicians' Desk Reference (2000), which is incorporated herein by reference in its entirety and include those directed against Lyme disease,

[0071] Hepatitis A, B, and C, HIV and Malaria.

[0072] In addition, appropriate target antigens comprise:

[0073] 1) proteins, lipoproteins, and glycoproteins, including viral, bacterial, parasitic, animal, and fungal proteins such as albumins, tetanus toxoid, diphtheria toxoid, pertussis toxoid, bacterial outer membrane proteins (including meningococcal outer membrane protein), RSV-F protein, malarial derived peptide, B-lactoglobulin B, aprotinin, ovalbumin, lysozyme, and tumor associated antigens such as carcinoembryonic antigen (CEA), CA 15-3, CA 125, CA 19-9, prostrate specific antigen (PSA), and the TAA complexes of U.S. Pat. No. 5,478,556, which is incorporated herein by reference in its entirety;

[0074] 2) carbohydrates, including naturally-occurring and synthetic polysaccharides and other polymers such as ficoll, dextran, carboxymethyl cellulose, agarose, polyacrylamide and other acrylic resins, poly (lactide-co-glycolide), polyvinyl alcohol, partially hydrolyzed polyvinyl acetate, polyvinylpryrolidine, Group B Steptococcal and Pneumococcal capsular polysaccharides (including type III), Pseudomonas aeruginosa mucoexopolysaccharide, and capsular polysaccharides (including fisher type I), and Haemophilus influenzae polysaccharides (including PRP);

[0075] 3) haptens, and other moieties comprising low molecular weight molecules such as TNP, saccharides, oligosaccharides, polysaccharides, peptides, toxins, drugs, chemicals, and allergens; and

[0076] 4) haptens and antigens derived from bacteria, rickettsiae, fungi, viruses, parasites, including Diphtheria, Pertussis, Tetanus, H. influenzae, S. pneumoniae, E. Coli, Klebsiella, S. aureus, S. epidermidis, N. meningiditis, Polio, Mumps, measles, rubella, Respiratory Syncytial Virus, Rabies, Ebola, Anthrax, Listeria, Hepatitis A, B, C, Human Immunodeficiency Virus I and II, Herpes simplex types 1 and 2, CMV, EBV, Varicella Zoster, Malaria, Tuberculosis, Candida albicans, and other candida, Pneumocystis carinii, Mycoplasma, Influenzae virus A and B, Adenovirus, Group A streptococcus, Group B streptococcus, Pseudomonas aeryinosa, Rhinovirus, Leishmania, Parainfluenzae, types 1, 2 and 3, Coronaviruses, Salmonella, Shigella, Rotavirus, Toxoplasma, Enterovirusses, and Chlamydia trachomatis and pneumoniae.

[0077] Moreover, because the HDRs of the invention non-specifically stimulate the immune response independent of the administration of an antigen, the compositions of the present invention can be used to treat, prevent, or ameliorate the symptoms resulting from exposure to a bio-warfare agent. Bio-warfare agents include those naturally occurring biological agents that have been specifically modified in the laboratory. Often, modification of these agents has altered them such that there is no known treatment. Examples include Ebola, Anthrax, and Listeria.

[0078] The HDRs of the invention may be administered prior to suspected exposure to a bio-warfare or other infectious agent to globally stimulate the immune system. Such treatment may be particularly efficacious in minimizing the morbidity, mortality, or symptoms associated with a low dose of the infectious agent. In the course of ameliorating the symptoms after exposure, use of the present HDRs may not cure the patient, but rather can extend the patient's life sufficiently such that some other treatment can then be applied.

[0079] Similarly, the administration of HDRs to patients traveling may prevent or minimize the effect of contact with unfamiliar infectious agents. In one embodiment, HDR-stimulated innate immunity protects the traveler from parasitic infection.

[0080] As suggested above, the immunogenic compositions of the present invention can be used to treat, prevent, or ameliorate any suitable infectious disease, including, but not limited to francisella, schistosomiasis, tuberculosis, AIDS, malaria, sepsis, and leishmania. Examples of suitable infectious viruses, bacteria, fungi, and other organisms (e.g., protists) can be found in International Patent Application WO 98/18810, which is incorporated herein by reference in its entirety. Optionally, the present method can be used in combination with any suitable anti-infectious agent. Suitable anti-infectious agents include those substances given in treatment of the various conditions described elsewhere, examples of which can be found in the Physicians' Desk Reference (2000).

[0081] The present inventive method of inducing an immune response can be used to treat, prevent, or ameliorate any allergic reaction. In one embodiment, administration of one or more HDRs in the context of the allergenic antigen stimulates a class switching to non-IgE isotypes. The HDRs and antigen may be co-administered with CD40 ligand, or cytokines such as TGF-β, IL-2, IL-4, and IL-5 as taught in U.S. Pat. No: 5,874,085, which is incorporated herein by reference in its entirety. Optionally, the present inventive method can also be used in combination with any suitable anti-allergenic agent. Suitable antiallergenic agents include those substances given in treatment of the various allergic conditions described above, examples of which can be found in the Physicians' Desk Reference (2000).

[0082] An allergy, in the context of the present invention, refers to an acquired hypersensitivity to a substance (i.e., an allergen). Allergic conditions include eczema, allergic rhinitis or coryza, hay fever, bronchial asthma, uticaria (hives), food allergies, and other atopic conditions. The list of allergens is extensive and includes pollens, insect venoms, animal dander, dust fungal spores, and drugs (e.g., penicillin). Additional examples of natural, animal, and plant allergens applicable to the present invention can be found in International Patent Application WO 98/18810, which is incorporated herein by reference in its entirety. In one embodiment, the present inventive method is used to treat allergic asthma.

[0083] Administration of the HDRs of the invention can be used to treat any suitable tumor, cancer, or pre-cancerous lesion. Optionally, the present inventive method can be used in combination with any suitable anti-cancer agent. Cancers include cancers of the brain, lung (e.g., small cell and non-small cell), ovary, breast, prostate, and colon, as well as carcinomas and sarcomas. Preferably, the present inventive method is used to treat a solid tumor cancer. Suitable anti-cancer agents include those treatments and substances given in treatment of the various conditions described above including ionizing radiation, specifically targeted cytotoxic compounds, cisplatin-transferrin, fluoxetine, staurosporines, vinblastine, methotrexate, 5-fluorouracil, and leucovorin, further examples of which can be found in the Physicians' Desk Reference (2000).

[0084] When employing the HDRs of the present invention as an adjuvant or vaccine component for allergens, haptens, poorly immunogenic peptides, and polysaccharides, the target molecules are preferably conjugated to strong T cell dependent antigens or otherwise complexed to increase their immunogenicity. Haptenic moieties, and other poorly immunogenic molecules, such as polysaccharides may be conjugated to strong T cell dependent antigens or otherwise complexed to increase their immunogenicity, as discussed, for example, by Dick and Bueret in Conjugate Vaccines, Contrib. Microbiol. Immunol. 10:48-114 (1989), Cruse J M and Lewis R E, Jr. eds., which is incorporated herein by reference in its entirety. Moreover, it has recently been shown that conjugation of a T-cell dependent antigen to a poorly immunogenic T cell-independent antigen, (e.g., a polysaccharide) can enhance the immunogenic response to both the T-cell dependent and T-cell independent components. In addition, the antibody response to additional moieties, including poorly immunogenic molecules and haptens (including non-T-cell dependent peptides) can also be dramatically enhanced if further conjugated to the T-cell dependent or T-cell independent carrier, or both, in a “dual conjugate” composition. Lees et al., Vaccine 1160-66 (1994); U.S. Pat. Nos. 5,585,100 and 5,955,079 to Mond and Lees, each of which is incorporated herein by reference in its entirety. This enhanced response is particularly pronounced when B cell epitopes of the additional moieties are intrinsically multivalent or otherwise present in multiple copies, although neither of these properties is absolutely required in the practice of the present invention.

[0085] As used herein, a moiety is any substance that is able to stimulate the immune system either by itself or once coupled to an immunogenic molecule. Thus, a moiety comprises an HDR or at least one T or B cell epitope and encompasses haptens, antigens, or combinations thereof. In some embodiments, an HDR is co-administered with, and may be electrostatically or chemically bound as a moiety to an immunogenic dual conjugate composition.

[0086] Additional Immunomodulators and Cell Targeting Elements

[0087] The immune response elicited by the HDRs and HDR-containing constructs of the invention may be further enhanced by the administration of immunomodulators and/or cell targeting moieties. Where an antigen-specific response is desired, these additional entities are co-administered with, and preferably chemically conjugated to, the antigen or immunogenic composition. Acceptable additional entities (moieties) include, for example, (1) LPS and detoxified lipopolysaccharides or derivatives thereof, (2) muramyl deputies, (3) carbohydrates and lipids (including cationic and anionic lipids, sterols, and the like) that may interact with cell surface determinants to target the construct to immunologically relevant cells; (4) proteins or polypeptides having specific immunological stimulatory activity including, for example, CD40 ligand, and fragments thereof, and polypeptides which bind to the CR2 receptor, including those described in copending U.S. Application No. 09/328,599 entitled: Enhancement of B Cell Activation and Immunoglobulin Secretion by Co-stimulation Of Receptors for Antigen and EBV Gp350/220, filed Jun. 10, 1999, in the names of Drs. James Mond and Andrew Lees, which is incorporated herein by reference in its entirety (5) peptides encoding limitation signals, for example, signals for farnesylation, geranylgeranylation, myristolation, or palmitoylation as described in U.S. Pat. No. 5,776,675, incorporated herein by reference in its entirety; (6) a universal TCE or Pan DR epitope, as described, for example in U.S. Pat. No. 5,114,713 to Sinigaglia; Alexander et al., Immunity 1:751-761 (1994); Ahlborg et al., Infect Immun 68:2102-9 (2000); Kaumaya et. al., J Mol Recognit. 6:81-94 (1993); Greenstein et al., J. Immunol. 148:3970-7 (1992) (each of which is incorporated herein by reference in its entirety); (7) antibodies that interact with cell surface components including, but not limited to, antibodies directed to CR2, CR2 receptors or other components of the antigen receptor complex, CD40 or CD40 ligand, and MHC components; and (8) one or more interleukins, including, but not limited to IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-9, IL-10, IL-12, IL-13, IL-15, GM-CSF, IFN-γ, TNF-α, TNF-β, and GM-CSF, especially combinations of GM-CSF with IL-2, and other immunostimulatory combinations described in copending U.S. application Ser. No. 08/568,343, to Mond and Snapper, filed May 10, 2000, entitled: Compositions For Stimulating The Release of Antibody By B Lymphocytes (which is incorporated herein by reference in its entirety ).

[0088] In one embodiment, the immunogenicity of a protein, hapten, or immunogenic composition may be further enhanced by the co-administration of an adjuvanting lipoprotein, as described in the copending U.S. applications Ser. Nos. 09/039,247 and 09/244,773, filed Feb. 5, 1999, and Mar. 16, 1998, respectively, each of which is incorporated herein by reference in its entirety. The lipoprotein may be covalently conjugated to the target protein, hapten, or composition, using, for example the methods described in U.S. Pat. No. 5,693,326 to Lees (incorporated herein by reference in its entirety).

[0089] Patient

[0090] The invention also relates to the treatment of a host by administration of an immunostimulatory amount of an HDR. A host encompasses both in vivo and ex vivo cells of the immune system, and thus includes the entire range from immortalized or freshly isolated cultured cells through intact organisms having an immune system. Host organisms may be patients, hereby defined as any person or non-human animal in need of immune stimulation, or to any subject for whom treatment may be beneficial, including humans and non-human animals. Such non-human animals to be treated include all domesticated and feral vertebrates, preferably, but not limited to: mice, rats, rabbits, fish, birds, hamsters, dogs, cats, swine, sheep, horses, cattle, and non-human primates.

[0091] The present invention is illustrated by the following Examples, which are not intended to be limiting in any way.

EXAMPLE 1

[0092] Oligonucleotide Design Synthesis

[0093] Phosphorothioate-substituted oligonucleotides were used to illustrate the surprising and unexpected properties of the RNA/DNA hybrids of the invention. In the following ODN and RDR and RNA sequences, DNA is depicted in capital letters and RNA in lower case. (SEQ ID NO:1) 5′ AAAAAAAAAAAAAACGTTAAAAAAAAAAAA 3′ DDD (SEQ ID NO:2) 5′ aaaaaaaaaaaaAACGTTaaaaaaaaaaaa 3′ RDR (SEQ ID NO:3) 5′ AAAAAAAAAAAAaacguuAAAAAAAAAAAA 3′ DRD (SEQ ID NO:4) 5′ aaaaaaaaaaaaaacguuaaaaaaaaaaaa 3′ RRR (SEQ ID NO:5) 5′ ggggggggggggAACGTTgggggggggggg 3′ 75GS (SEQ ID NO:6) 5′ aaaaaaaaaaaaCCCGGGaaaaaaaaaaaa 3′ 74CG (SEQ ID NO:7) 5′ aaaaaaaaaaaaaaCGaaaaaaaaaaaaaa 3′ 7401 (SEQ ID NO:8) 5′ GGGGGGGGGGGGaacguuGGGGGGGGGGGG 3′ 75DNA (SEQ ID NO:9) 5′ ctctctctctctaacguuctctctctctct 3′ 76CT (SEQ ID NO:10) 5′ ggggggggggggaacguugggggggggggg 3′ 75RNA (SEQ ID NO:11) 5′ AAAAAAAAAAAAAAGCTTAAAAAAAAAAAA 3′ DDDC

[0094] The control oligonucleotide, DDD (SEQ ID NO:1), is composed entirely of deoxyribonucleotides. Two representative HDRs, each with a core hexamer sequence identical to that of the control ODN were used in direct comparisons with DDD (SEQ ID NO:1): RDR (SEQ ID NO:2), comprises primarily RNA but contains an internal DNA cassette having the base sequence AACGTT and DRD (SEQ ID NO:3), which is the inverse of RDR, and comprises DNA sequences flanking an internal aaggct sequence of ribonucleotides. RRR (SEQ ID NO:4) comprises the same base sequence of SEQ ID NO:1, but is synthesized entirely from RNA. As noted above, ODN sequences comprised of RNA are widely considered inoperative.

[0095] Seven additional ODNs, SEQ ID NOS: 5-11, were generated to assay the relationship between base composition and HDR function.

[0096] DDD (SEQ ID NO:1), RDR (SEQ ID NO:2), and DRD (SEQ ID NO:3) were generated on a commercially-available PE/ABI 394 RNA/DNA Synthesizer. DNA precursors were attached at bottle positions 1-4 and RNA precursors, having a protective silyl group for protection of the 2′ position, were attached at the bottle positions 5-8. The remaining bottle positions contained standard chemicals for beta-cyanoethyl diisopropyl phosphoramidite chemistry synthesis, with the exception of bottle No. 15, which contained Beaucage Reagent (1 g/100 ml in acetonitrile) as a sulfurization agent as described in U.S. Pat. No. 5,003,097 (incorporated herein by reference in its entirety). RNA precursors and Beaucage Reagent was purchased from Glen Research of Sterling Va. Acetonitrile was purchased from Burdick & Jackson through VWR Scientific. The remaining chemicals were from PE/ABI (Foster City, Calif.).

[0097] The 1 μM Sulfur Synthesis Program provided by PE/ABI is adequate for the preparation of any HDR, as are the general methods provided in Applied Biosystems' User Bulletin 53 and Applied Biosystems Bulletin No. 6: Chemistry for Automated DNA/RNA Synthesis, Mar. 1994. (incorporated herein by reference in its entirety) for EXPEDITE®, PHARMACIA®, and BECKMAN® synthesizers. Nevertheless, a number of modifications were employed to increase yields:

[0098] 1) The wash step of rinsing the column matrix with acetonitrile was increased by approximately 30%.

[0099] 2) Capping time was doubled from 5 seconds to 10 seconds.

[0100] 3) The recommended coupling time of 25 seconds for DNA and 600 seconds for RNA was increased to 725 seconds for all additions.

[0101] 4) Beaucage Reagent replaced TETD as the sulfurization reagent. Although the usual sulfurization time is 600 seconds for TETD or 20-30 seconds for Beaucage Reagent, sulfurization was extended to 60 seconds with Beaucage.

[0102] 5) Oligonucleotides were cleaved from the synthesis column matrix using a 3:1 ratio of 30% NH₄OH:ethanol. Exocyclic amine protective groups were removed via heat in the cleavage solution for 18 hours at 55° C. After cooling to room temperature, the oligonucleotides were dried completely in a speed-vac evaporator.

[0103] 6) The 2′ silyl protective group was removed with 300 μl Tetrabutylammonium Fluoride (TBAF) at room temperature for 22 hours using a test tube rotator to gently agitate the solution.

[0104] 7) The samples were applied to a PD10 column (Pharmacia/Amersham) to remove the TBAF and other contaminants resulting from synthesis or ammonolysis. Water used for elution was filtered through 2 sterile “stacked” Millex-GV 0.22 μm filters.

[0105] 8) Oligonucleotides were visualized using PAGE on a 20% polyacrylamide/8M urea gel, which was stained with 1% methylene blue and destained in water.

[0106] Oligonucleotide RRR (SEQ ID NO:4) was synthesized using a similar method.

[0107] The relative efficacy of the HDRs of the invention may be tested using the standard methods employed in the following Examples. In particular, treatment of the various T cell populations with one or more HDRs will induce the production of Th1 and/or Th2-type cytokines, for example, IFN-γ and IL-6, respectively.

[0108] Of course, one of ordinary skill understands that numerous additional in vitro and in vivo assays may also be used to assess the efficacy of a composition within the scope of the invention, as well as the appropriate dosage schedule and an amount sufficient to produce an optimal response. For example, B cell activation may be assessed using methods known in the art (see for example, Liang et a., J. Clin. Invest. 98:1119-29 (1996) (which is incorporated herein by reference in its entirety)). NK activity may be determined as described in WO 98/18810 (which is incorporated herein by reference in its entirety). The effects of HDRs on dendritic cells, macrophages, and monocytes may be determined as described in Stacey et al., J. Immunol. 157:2116 (1996); Chace et al., Clin. Immunol. Immunopathol. 84:185 (1997); Hacker et al., EMBO J. 17:6230 (1998); and Behboudi et al., Immunol. 99:361-66 (2000) (each of which is incorporated herein by reference in its entirety). By comparing the type, amount, and ratios of cytokines and cell surface molecules produced, it will be evident that the HDRs of the invention are useful in stimulating innate and acquired, humoral and cellular immunities. Moreover, one of skill in the art may thereby select the most potent HDR sequences to match the type of immune stimulation desired (Verthelyi et al., J. of Immunology 166: 2372-77 (2001)). Because each HDR will stimulate the immune system in a particular manner (e.g., resulting in a profile of cytokine secretion and/or suppression from one or more T, B, NK, or monocyte populations), it is not only possible to select the most appropriate HDR for a particular type of immune stimulation, but multiple HDRs may be combined to elicit a desired pattern of immune stimulation.

[0109] The in vitro assays may be done using human or animal cells (e.g. B, T, NK, oligodendrocytes, or monocytes) isolated according to standard methods in the art. Tester cells may be freshly isolated human peripheral lymphocytes or mouse spleen cells. Depending on the requirements of any particular assay or application, cells may be of mixed population or purified to 99% or greater purity as described in Snapper et al., J. Immunol. 1158:2731-35 (1997) (which is incorporated herein by reference in its entirety). NK cells may be prepared according to Snapper et al., J. Immunol. 151:5212-60 (1993) (which is incorporated herein by reference in its entirety).

[0110] Alternatively, previously characterized or established immune cell lines may be employed, for example, B cell lines, or T cell lines, including Th1 cell clones or Th2 cell clones (e.g., AF7 cells).

EXAMPLE 2

[0111] Hybrid DNA/RNA Oligonucleotides Stimulate TH1 and TH2-type Cytokine Production

[0112] The stimulation of cytokines IL-6 and IFN-γ in human peripheral lymphocytes cultured from four healthy volunteer subjects, designated S1 through S4, was assayed using standard methods. Briefly, oligonucleotides DDD and RDR of Example 1 were added to the media of cultured cells to final concentrations of 0.3, 3, or 30 μg/ml. 24 hours after oligonucleotide addition, Th1 and Th2-type cytokine levels in the media were determined by ELISA. Results are presented in arbitrary ELISA UNITS (EU) in Table I and Table II below. TABLE I Hybrid DNA/RNA Oligonucleotide Stimulates Release of IL-6 S1 S2 S3 S4 media control 0.061 0.048 0.105 0.106 DDD (0.3 μg/ml) 0.157 0.137 0.123 0.197 (SEQ ID NO: 1) DDD (3.0 μg/ml) 0.111 0.130 0.147 0.176 (SEQ ID NO: 1) DDD (30 μg/ml) 0.154 0.145 0.190 0.428 (SEQ ID NO: 1) RDR (0.3 μg/ml) 0.077 0.117 0.164 0.217 (SEQ ID NO: 2) RDR (3.0 μg/ml) 0.656 1.168 0.692 1.023 (SEQ ID NO: 2) RDR (30 μg/ml) 1.547 1.305 1.595 1.568 (SEQ ID NO: 2)

[0113] TABLE II Hybrid DNA/RNA Oligonucleotide Stimulates Release of IFN-γ S1 S2 S3 S4 media control 0.061 0.048 0.105 0.106 DDD (0.3 μg/ml) 0.218 0.559 0.234 0.133 (SEQ ID NO: 1) DDD (3.0 μg/ml) 0.279 0.447 0.249 0.158 (SEQ ID NO: 1) DDD (30 μg/ml) 0.298 0.455 0.337 0.314 (SEQ ID NO: 1) RDR (0.3 μg/ml) 0.25 0.558 0.237 0.153 (SEQ ID NO: 2) RDR (3.0 μg/ml) 0.762 1.21 0.505 0.191 (SEQ ID NO: 2) RDR (30 μg/ml) 1.592 1.198 0.792 0.492 (SEQ ID NO: 2)

[0114] As is evident from the results in Table I and Table II, the hybrid DNA/RNA oligonucleotides of the invention stimulate the production of cytokines implicated in eliciting both Th1 (IFN-γ) and Th2 T (IL-6) type responses in human peripheral lymphocytes.

[0115] Moreover, a comparison of the results obtained with the hybrid RDR molecule and the DNA control sequence, DDD, reveals the surprising and unexpected superiority of the HDRs of the invention over ODNs. At the highest concentrations tested, for example, the hybrid RDR molecule was 3-fold more effective at inducing IFN-γ and 6-fold more effective at stimulating the release of IL-6. Consequently, it is expected that the HDRs of the invention, including mixtures of HDRs that elicit complementary patterns of activation, will provide correspondingly superior improvement to Th1 and Th2 responses in a patient as compared to DNA-based oligonucleotides.

EXAMPLE 3

[0116] Hybrid DNA/RNA Oligonucleotides Stimulate B Cell Proliferation

[0117] The human peripheral B cell populations of Example 2 were assayed for proliferation in the thymidine incorporation assay as described in Brunswick et al., J. Immunol. 140:3364-72 (1988); and Snapper et al., J. Immunol. 155:5582-89 (1995) (each of which is incorporated herein by reference in its entirety). As is evident from the data in Table III, the HDRs of the invention can stimulate a nearly 10-fold increase in B cell replication, as measured by tritiated thymidine incorporation. As shown in Table IV, comparable results were obtained using mouse B cells. Note that the data in Table IV also demonstrate the superiority of oligonucleotide RDR over DRD in this particular assay.

[0118] Consequently, administration of HDRs as adjuvants or vaccine components will stimulate the clonal expansion of antigen-specific B cells, thus promoting the production of antibodies and effectively increasing the immunogenicity of a target antigen. In addition, the HDRs will globally stimulate B cells to divide, thereby increasing innate humoral immunity. TABLE III Hybrid DNA/RNA Oligonucleotide Stimulates B Cell Proliferation S1 S2 S3 S4 media control 364 1578 864 872 DDD (0.3 μg/ml) 596 1646 970 716 (SEQ ID NO: 1) DDD (3.0 μg/ml) 3660 15954 8926 2331 (SEQ ID NO: 1) DDD (30 μg/ml) 11571 24243 28140 8378 (SEQ ID NO: 1) RDR (0.3 μg/ml) 805 3055 806 1199 (SEQ ID NO: 2) RDR (3.0 μg/ml) 2794 12397 8426 3329 (SEQ ID NO: 2) RDR (30 μg/ml) 2359 3687 3434 1892 (SEQ ID NO: 2)

[0119] TABLE IV media control 131 DDD (30 ug/ml) 6897 (SEQ ID NO: 1) DDD (3 ug/ml) 1998 (SEQ ID NO: 1) DDD (.3 ug/ml) 176 (SEQ ID NO: 1) RDR (30 ug/ml) 7436 (SEQ ID NO: 2) RDR (3 ug/ml) 3924 (SEQ ID NO: 2) RDR (.3 ug/ml) 235 (SEQ ID NO: 2) DRD (30 ug/ml) 172 (SEQ ID NO: 3) DRD (3 ug/ml) 173 (SEQ ID NO: 3) DRD (.3 ug/ml) 134 (SEQ ID NO: 3) 75RNA (30 ug/ml) na (SEQ ID NO: 10) 75RNA (3 ug/ml) 215 (SEQ ID NO: 10) 75RNA (.3 ug/ml) 170 (SEQ ID NO: 10) RRR (30 ug/ml) 236 (SEQ ID NO: 4) RRR (3 ug/ml) 206 (SEQ ID NO: 4) RRR (.3 ug/ml) 160 (SEQ ID NO: 4)

EXAMPLE 4

[0120] Hybrid DNA/RNA Oligonucleotides Stimulate Antibody Secretion

[0121] The ability of HDRs to activate B cells to produce antibody was illustrated using the polyclonal activation and ELISA assays essentially as described in Pecanha et al., J. Immunol. 146:883-89 (1991); and Snapper et al., J. Immunol. 154:5842-50 (1995) (each of which is incorporated herein by reference in its entirety). The techniques described in Finkelman et al., J. Immunol. 138:2826-30 (1987) (which is incorporated herein by reference in its entirety), are also appropriate. In addition, methods for assaying for the stimulation of antibody production and class switching, especially IgA class switching, are evident from U.S. Pat. No. 5,874,085 to Mond and Snapper, which is incorporated herein by reference in its entirety. TABLE V IgM Secretion From Human Peripheral B Cells (in μg/ml) S1 S2 S3 S4 media control 0.584 0.455 0.574 0.461 DDD (0.3 μg/ml) 0.652 0.470 0.583 0.446 (SEQ ID NO: 1) DDD (3.0 μg/ml) 1.031 0.772 1.003 0.5 (SEQ ID NO: 1) DDD (30 μg/ml) 1.523 0.650 1.745 0.647 (SEQ ID NO: 1) RDR (0.3 μg/ml) 0.556 0.450 0.584 0.437 (SEQ ID NO: 2) RDR (3.0 μg/ml) 0.702 0.470 0.743 0.444 (SEQ ID NO: 2) RDR (30 μg/ml) 0.507 0.395 0.506 0.45 (SEQ ID NO: 2)

[0122] As shown in Table V, the RDR oligonucleotide did not elicit antibody secretion substantially above background in this particular experiment (values are in arbitrary ELISA units). This lack of effect may be due to experimental error, or a lack of sensitivity of the assay. Nevertheless, in a subsequent experiment shown in Table VI, purified human peripheral B cells secreted up to 22-fold more antibody following exposure to the RDR oligonucleotide. TABLE VI IgM Secretion From Purified Human Peripheral B Cells (in μg/ml) P1 P2 P3 media control 15 9 25 DDD (0.3 μg/ml) 14 8 30 (SEQ ID NO: 1) DDD (3.0 μg/ml) 33 20 80 (SEQ ID NO: 1) DDD(30 μg/ml) 100 160 1500 (SEQ ID NO: 1) RDR (0.3 μg/ml) 12 9 23 (SEQ ID NO: 2) RDR (3.0 μg/ml) 38 23 90 (SEQ ID NO: 2) RDR (30 μg/ml) 215 48 550 (SEQ ID NO: 2)

EXAMPLE 5

[0123] Hybrid DNA/RNA Oligonucleotides Stimulate Individual T Cells to Secrete Th1-type and Th2-type Cytokines

[0124] DBA/2 mouse spleen cells were treated with medium, or medium containing 3.0 μg/ml of RDR or control oligonucleotides. The cells were then subject to an enzyme-linked immunospot (ELISPOT) assay to identify cells expressing IL-6, IL-10, IL-12, and IFN-γ. Table VII reports the number of positive cells per 100,000 cells. ELISPOT assays are well known in the art. Representative methods are described in Czerkinsky et al., J. Immunol. Meth. 65:109-121 (1983); Sedgwich and Holt, J. Immunol. Meth. 57:301-309 (1983); Amano et al., J. Immunol. Meth. 144:127-140; Sparholt et al., Clin. Exp. Allergy, 21:85-90 (1991); and Jones et al., Autoimmunity, 31:117-124 (1999), each of which is incorporated herein by reference in its entirety. As is recognized by one of ordinary skill, the ELISPOT method may be modified to use any T cell type, subtype, or established T cell tester line. Moreover, antibodies directed against any relevant cytokine may be used to test the efficacy of a particular HDR to be assayed. TABLE VII Hybrid DNA/RNA Oligonucleotide Stimulates Substantially More Th1 and Th2 Cells Than A Corresponding DNA-based Adjuvant IL-6 IL-10 IL-12 IFN-γ medium 144 128 144 109 DDD (SEQ ID NO: 1) 256 3 256 52 RRR (SEQ ID NO: 4) 160 1 235 5 RDR (SEQ ID NO: 2) 8976 3 2564 140

[0125] The control ODN, DDD (SEQ ID NO.1), provides to a roughly ⅔-fold increase in the number of T cells expressing IL-6 (a Th1-type cytokine) and IL-12 (a Th2-type cytokine). DDD also reduced by half the number of cells expressing IFN-γ and substantially reduced IL-10 production. As expected, the RNA-based oligonucleotide did not stimulate IL-6 production. Interestingly, it did induce some cells to secrete IL-12 and virtually ablated IL-10 and IFN-γ expression. These results are essentially consistent with the view that RNA-based adjuvants are clinically irrelevant.

[0126] In surprising contrast to the effects of single-sugar constructs, the RNA/DNA hybrid of the invention, RDR (SEQ ID NO:2), did not reduce (and, in fact, increased) the number of cells expressing IFN-γ and dramatically increased the proportion of cells secreting both IL-6 and IL-12. Indeed, as compared with the DDD control of the same base sequence, treatment with the HDR construct induced 10-fold more cells to secrete IL-12, and fully 35-fold more cells to express IL-6. This dramatic and unexpected increase in the number of responsive T cells is indicative of the clinical advantage enjoyed by the compositions of the invention in stimulating humoral and cellular immune responses.

EXAMPLE 6

[0127] Dose-response Study of DDD and DRD Oligonucleotide Adjuvants

[0128] Table VIII presents the results of a dose-response experiment performed essentially as described for Example 5. Briefly, these results confirm the superiority of the RNA:DNA hybrids of the invention in stimulating cells of the immune system to secrete IL-6 and IL-12. (Data are number of positive cells per 100,000.) This effect is most pronounced at higher nucleotide concentrations, suggesting that local concentrations in excess of 3 μg/ml may be most efficacious. Curiously, the RDR (SEQ ID NO:2) and the DDD (SEQ ID NO:1) control were roughly equally stimulatory of IFN-γ production at the higher concentrations tested. TABLE VIII IL-6 IL-12 IFN-γ medium 1292 657 168 DDD (3.0 μg/ml) 8750 2195 688 (SEQ ID NO: 1) DDD (0.3 μg/ml) 3798 2035 360 (SEQ ID NO: 1) DDD (0.03 μg/ml) 2083 962 176 (SEQ ID NO: 1) DDD (0.003 μg/ml) 1522 652 72 (SEQ ID NO: 1) DDD (0.0003 μg/ml) 1387 737 136 (SEQ ID NO: 1) RDR (3.0 μg/ml) 11250 3397 552 (SEQ ID NO: 2) RDR (0.3 μg/ml) 3990 3237 544 (SEQ ID NO: 2) RDR (0.03 μg/ml) 1410 1186 232 (SEQ ID NO: 2) RDR (0.003 μg/ml) 833 625 144 (SEQ ID NO: 2) RDR (0.0003 μg/ml) 978 545 232 (SEQ ID NO: 2)

EXAMPLE 7

[0129] HDR Function is Related to Structure

[0130] The activity of ODNs is known to vary with sequence. To assess whether HDR activity also varies based on sequence a number of different HDRs were designed and tested for their ability to stimulate individual T cells to secrete Th1-type and Th2-type cytokines. This experiment was performed similarly to the one described in Example 5, with the exception that human PBLs were used. As shown in Table IX, the ability of HDRs to stimulate Th1-type and Th2-type cytokine production is highly dependent on HDR sequence. (Data are number of positive cells per 100,000.) HDRs can thus be designed to preferentially stimulate Th-1 vs. Th-2 type responses. Moreover, HDRs eliciting different, even complimentary, patterns of cytokine stimulation can be used in concert to stimulate a desired immune response. TABLE IX IL-6 IL-12 media control 1944 408 DDD (30 ug/ml) 1215 918 (SEQ ID NO: 1) DDD (30 ug/ml) 1944 1122 (SEQ ID NO: 1) RDR (30 ug/ml) 3159 1326 (SEQ ID NO: 2) DRD (30 ug/ml) 2552 765 (SEQ ID NO: 3) 74CG (30 ug/ml) 2066 618 (SEQ ID NO: 6) 74C1 (15 ug/ml) 4860 9 (SEQ ID NO: 7) 74C1 (30 ug/ml) 2309 8 (SEQ ID NO: 7) 75DNA (30 ug/ml) 3281 765 (SEQ ID NO: 8) 76CT (15 ug/ml) 4253 2040 (SEQ ID NO: 9) 76CT (26.7 ug/ml) 2187 10 (SEQ ID NO: 9)

EXAMPLE 8

[0131] HDRs Stimulate Innate Immunity in vivo

[0132] An HDR is suspended in phosphate buffered saline and injected intraperitoneally into DBA/2 mice at a dose of 2-500 μg/animal. Twenty-four hours later spleen cells from some of the injected mice and mock-injected PBS controls are analyzed for expression of B cell surface activation markers Ly-6A/E, Bla-1, and class II MHC, using three-color flow cytometry, and for spontaneous proliferation activity using a standard tritiated thymidine assay. Expression of activation markers will be significantly increased in the HDR injected mice as opposed to the controls. Similarly, cells from the HDR injected animals will incorporate significantly more labeled thymidine. Samples of spleen cells from injected mice are analyzed for NK activity using, for example, the short term chromium release assay described by Ballas et al., J. Immunol. 150:17 (1993) (which is incorporated herein by reference in its entirety). Cells from HDR injected animals will show increased levels of NK cell activation as compared to controls.

[0133] Four days after injection, serum is collected from the remaining mice and analyzed for total IgM by ELISA or Octerlony assay. HDR injected mice will show increased levels of total IgM as opposed to the PBS injected controls.

EXAMPLE 9

[0134] HDRs Stimulate Innate Immunity in vivo

[0135] A single administration of a CpG ODN can confer immune protection against L. monocytogenes infection in mice that lasts for up to two weeks (Krieg et al., J. of Immunology, 161: 2428-2434 (1998)) (incorporated herein by reference in its entirety). If the ODN is administration in repeated this resistance can be maintained indefinetly (Kinman et al., Infection and Immunity, 67: 5658-63 (1999)) (incorporated herein by reference in its entirety).

[0136] To demostrate that the HDRs of the invention are similarly capable of stimulating innate immunity, we employed the technique described in Klinman et al., Infection and Immunity, 67: 5658-63 (1999), which assays resistance to bacterial challenge. Briefly, BALB/c mice were injected with various agents (as described in Table X) and challenged 5 days later with 1,000 LD 50's of L. monocytogenes. As seen in Table X, a single administration of either DDD (SEQ ID NO:1) or RDR (SEQ ID NO:2) (a representative example of an HDR) is capable of conferring resistance in most or all of the mice tested for, at a minimum, 5 days following administration. As expected, the effects of the oligonucleotides could not be demonstrated by 4 weeks post-administration. As demonstrated in Table X, administeration of the ODN in the context of a liposome, which significantly extends the period over which stimulatory material is released, extends the period of detectable increased innate immunity to at least 4 weeks. Administration of HDRs of the invention in the context of liposomes, depot adjuvants such as alum, cochleates, conjugates, linkage to large polymers such as polyethylene glycol (PEGylation), time sensitive delivery formulation, or other forms which delay the release or degradation of the HDR will also extend the period of immune stimulation, as will repeated administrations of the stimulatory HDR. TABLE X 5 days 4 weeks saline control 0/5 0/5 DDD (SEQ ID NO: 1) 5/5 0/5 RDR (SEQ ID NO: 2) 4/5 0/5 DDDC (SEQ ID NO: 11) 1/5 0/5 DDD (SEQ ID NO: 1) - 5/5 5/5 liposome DDD (SEQ ID NO: 1) - 0/5 0/5 liposome

EXAMPLE 10

[0137] HDRs Stimulate Antibody Production and Class Switching in vivo

[0138] An HDR is suspended in phosphate buffered saline along with bovine serum albumin (BSA). A dose comprising approximately 2-500 μg of oligonucleotide and 1-25 μg of protein is injected subcutaneously into Balb/c mice. Control mice are injected with a corresponding dose of protein without nucleotide. Additional groups of mice co-injected with protein, or protein plus HDR, are coinjected with GM-CSF, and GM-CSF and IL-2, or other cytokines and cytokine combinations. Injections are repeated after 14 days.

[0139] Serum collected two weeks later is tested by ELISA for antibodies reactive against the target antigen. ELISA assays are also used to determine the relative, or preferably, the absolute level of anti-BSA antibodies of each isotype. HDR injected animals will show elevated levels of anti-BSA antibody, in particular increased levels of IgA and/or IgG antibodies, and may show increased levels of IgG₁, IgG₂, and/or IgG_(2a) isotypes.

EXAMPLE 11

[0140] Representative HDRs of the Invention

[0141] The following HDRs are representative of the invention and not limiting in any way. These illustrative sequences have been selected in light of ODN sequences known in the art to posses immunostimulatory activity (innate, global, cellular and/or humoral), and in light of the surprising observation reported herein that hybrid RNA-DNA ONDs (HDRs) possess robust immunostimulary activity both in vitro an in vivo. Using the teachings of Examples 1-10, or other assays commonly used in the art, the skilled artisan will recognize that such HDRs, and all other HDR sequences within the scope of the invention can be assayed in vitro or in vivo for immunostimulatory activity.

[0142] In the following sequences, “t” refers to thymidine linked to at least one other base through a ribose sugar. There present invention further contemplates HDRs wherein any “u” (uracil) replaces any “t”, and, further, where “i” (inosine linked to at least one other base through a ribose sugar), replaces any ribose-linked base in the following exemplary sequences. TCAACGTTaacgtt (SEQ ID NO:12) TCCATGACGTTCCTGATGCTaacgtt (SEQ ID NO:13) ATCGACTCTCGAGCGTTCTCaacgtt (SEQ ID NO:14) GCATGACGTTGAGCTaacgtt (SEQ ID NO:15) TCAGCGCTaacgtt (SEQ ID NO:16) GAGAACGCTGGACCTTCCATaacgtt (SEQ ID NO:17) GAGAACGCTCGACCTTCCATaacgtt (SEQ ID NO:18) GAGAACGCTCGACCTTCGATaacgtt (SEQ ID NO:19) GAGAACGCTCCAGCACTGATaacgtt (SEQ ID NO:20) TCCATGTCGGTCCTGATGCTaacgtt (SEQ ID NO:21) TCCATGTCGGTCCTGCTGATaacgtt (SEQ ID NO:22) ATGGACTCTCCAGCGTTCTCaacgtt (SEQ ID NO:23) ATGGAAGGTCCAACGTTCTCaacgtt (SEQ ID NO:24) gctagacGTTAGCGT (SEQ ID NO:25) tcaacGTT (SEQ ID NO:26) tccatgacGTTCCTGATGCT (SEQ ID NO:27) atcgactctcGAGCGTTCTC (SEQ ID NO:28) gcatgacGTTGAGCT (SEQ ID NO:29) tcagcGCT (SEQ ID NO:30) gagaacGCTGGACCTTCCAT (SEQ ID NO:31) gagaacGCTCGACCTTCCAT (SEQ ID NO:32) gagaacgctcGACCTTCGAT (SEQ ID NO:33) gagaacGCTCCAGCACTGAT (SEQ ID NO:34) tccatgtcGGTCCTGATGCT (SEQ ID NO:35) tccatgtcGGTCCTGCTGAT (SEQ ID NO:36) atggactctccagcGTTCTC (SEQ ID NO:37) atggaaggtccaacGTTCTC (SEQ ID NO:38) tccatggcGGTCCTGATGCT (SEQ ID NO:39) tccatgacGGTCCTGATGCT (SEQ ID NO:40) tccatgtcGATCCTGATGCT (SEQ ID NO:41) tccatgtcGCTCCTGATGCT (SEQ ID NO:42) tccatgtcGTTCCTGATGCT (SEQ ID NO:43) tccataacGTTCCTGATGCT (SEQ ID NO:44) tccatgacGTCCCTGATGCT (SEQ ID NO:45) TCCATGGCGGTCCTGATGCTaacgtt (SEQ ID NO:46) TCCATGACGGTCCTGATGCTaacgtt (SEQ ID NO:47) TCCATGTCGATCCTGATGCTaacgtt (SEQ ID NO:48) TCCATGTCGCTCCTGATGCTaacgtt (SEQ ID NO:49) TCCATGTCGTTCCTGATGCTaacgtt (SEQ ID NO:50) TCCATAACGTTCCTGATGCTaacgtt (SEQ ID NO:51) TCCATGACGTCCCTGATGCTaacgtt (SEQ ID NO:52) GCTAGACGTTAGCGTacaacgtt (SEQ ID NO:53) TCAACGTTacaacgtt (SEQ ID NO:54) TCCATGACGTTCCTGATGCTacaacgtt (SEQ ID NO:55) ATCGACTCTCGAGCGTTCTCacaacgtt (SEQ ID NO:56) GCATGACGTTGAGCTacaacgtt (SEQ ID NO:57) TCAGCGCTacaacgtt (SEQ ID NO:58) GAGAACGCTGGACCTTCCATacaacgtt (SEQ ID NO:59) GAGAACGCTCGACCTTCCATacaacgtt (SEQ ID NO:60) GAGAACGCTCGACCTTCGATacaacgtt (SEQ ID NO:61) GAGAACGCTCCAGCACTGATacaacgtt (SEQ ID NO:62) TCCATGTCGGTCCTGATGCTacaacgtt (SEQ ID NO:63) TCCATGTCGGTCCTGCTGATacaacgtt (SEQ ID NO:64) ATGGACTCTCCAGCGTTCTCacaacgtt (SEQ ID NO:65) ATGGAGGTCCAACGTTCTCacaacgtt (SEQ ID NO:66) TCCATGGCGGTCCTGATGCTacaacgtt (SEQ ID NO:67) TCCATGACGGTCCTGATGCTacaacgtt (SEQ ID NO:68) TCCATGTCGATCCTGATGCTacaacgtt (SEQ ID NO:69) TCCATGTCGCTCCTGATGCTacaacgtt (SEQ ID NO:70) TCCATGTCGTTCCTGATGCTacaacgtt (SEQ ID NO:71) acaacgttGCTAGACGTTAGCGT (SEQ ID NO:72) acaacgttTCAACGTT (SEQ ID NO:73) acaacgttTCCATGACGTTCCTGATGCT (SEQ ID NO:74) acaacgttATCGACTCTCGAGCGCGCTC (SEQ ID NO:75) acaacgttGCATGACGTTGAGCT (SEQ ID NO:76) accaacgttTCAGCGCT (SEQ ID NO:77) acaacgttGAGAACGCTGGACCTTCCAT (SEQ ID NO:78) acaacgttGAGAACGCTCGACCTTCCAT (SEQ ID NO:79) acaacgttGAGAAOGCTCGACCTTCGAT (SEQ ID NO:80) acaacgttGAGAACGCTCCAGCACTGAT (SEQ ID NO:81) acaacgttTCCATGTCGGTCCTGATGCT (SEQ ID NO:82) acaacgttTCCATGTCGGTCCTGCTGAT (SEQ ID NO:83) acaacgttATGGACTCTCCAGCGTTCTC (SEQ ID NO:84) acaacgttATGGAAGGTCCAACGTTCTC (SEQ ID NO:85) acaacgttTCCATGGCGGTCCTGATGCT (SEQ ID NO:86) acaacgttTCCATGACGGTCCTGATGCT (SEQ ID NO:87) acaacgttTCCATGTCGATCCTGATGCT (SEQ ID NO:88) acaacgttTCCATGTCGCTCCTGATGCT (SEQ ID NO:89) acaacgttTCCATGTCGTTCCTGATGCT (SEQ ID NO:90) GCTAgacgttAGCGT (SEQ ID NO:91) TCAAcgTT (SEQ ID NO:92) TCCATgacgttCCTGATGCT (SEQ ID NO:93) ATCGACTctcgagcgttCTC (SEQ ID NO:94) GCATgacgttGAGCT (SEQ ID NO:95) TCAGcgCT (SEQ ID NO:96) GAGaacgctGGACCTTCCAT (SEQ ID NO:97) GAGAACGctcgacCTTCCAT (SEQ ID NO:98) GAGAAcgctcgacCTTCGAT (SEQ ID NO:99) GAGAAcgCTCCAGCACTGAT (SEQ ID NO:100) TCCATgtcggtCCTGATGCT (SEQ ID NO:101) TCCATgtcggtCCTGCTGAT (SEQ ID NO:102) ATGGACtctccaGCGTTCTC (SEQ ID NO:103) ATGGAAggtccaaCGTTCTC (SEQ ID NO:104) TCCATggcgGTCCTGATGCT (SEQ ID NO:105) TCCATGacggtccTGATGCT (SEQ ID NO:106) TCCATGTcgatCCTGATGCT (SEQ ID NO:107) TCCATGtcgctccTGATGCT (SEQ ID NO:108) TCCAtgtcgTTCCTGATGCT (SEQ ID NO:109) TCCATAAcgTTCGTGATGCT (SEQ ID NO:110) TCCAtgacgtccctgatGCT (SEQ ID NO:111) gctaGACGTTagcgt (SEQ ID NO:112) tcAACGTT (SEQ ID NO:113) tccatGACGTTcctgatgct (SEQ ID NO:114) atcgactCTCGAGcgttctc (SEQ ID NO:115) gcatGACGTTgagct (SEQ ID NO:116) tcAGCGCT (SEQ ID NO:117) gagAACGCTggaccttccat (SEQ ID NO:118) gagaacgCTCGACcttccat (SEQ ID NO:119) gagaacgCTCGACcttcgat (SEQ ID NO:120) gagaacgctcCAGCACtgat (SEQ ID NO:121) gagaACGCTCcagcactgat (SEQ ID NO:122) gagaACGCTCCAGCACtgat (SEQ ID NO:123) tccatGTCGGTcctgatgct (SEQ ID NO:124) tccatGTCGGTcctgctgat (SEQ ID NO:125) atggactctccAGCGTTctc (SEQ ID NO:126) atggaaggtccAACGTTCtc (SEQ ID NO:127) tccatGGCGGTcctgatgct (SEQ ID NO:128) tccatGACGGTcctgatgct (SEQ ID NO:129) tccatGTCGATcctgatgct (SEQ ID NO:130) tccatGTCGCTcctgatgct (SEQ ID NO:131) tccatGTCGTTcctgatgct (SEQ ID NO:132) tccatAACGTTcctgatgct (SEQ ID NO:133) tccatGACGTCcctgatgct (SEQ ID NO:134) GCTAGACGTTagcgt (SEQ ID NO:135) TCAACGTTTCACGTaaaa (SEQ ID NO:136) aaaaTCAACGTTTCACGT (SEQ ID NO:137) TCCATGACGTTcctgatgct (SEQ ID NO:138) ATCGACTCTCGagcgttctC (SEQ ID NO:139) GCATGACGTTgagct (SEQ ID NO:140) TCAGCgct (SEQ ID NO:141) tcAGCGct (SEQ ID NO:142) GAGAACGCTGgaccttccat (SEQ ID NO:143) GAGAACGCTCGACcttccat (SEQ ID NO:144) GAGAACGCTCGACcttcgat (SEQ ID NO:145) GAGAACGctccagcactgat (SEQ ID NO:146) GAGAACGCTCcagcactgat (SEQ ID NO:147) GAGAACGCTCCAGCactgat (SEQ ID NO:148) GAGAACGCTCCAGCACtgat (SEQ ID NO:149) GAGAACGCTCCAGCACTGAttttttt (SEQ ID NO:150) GAGAACGCTCCAGCACTGaaaaaaa (SEQ ID NO:151) TCCATGTCGgtcctgatgct (SEQ ID NO:152) TCCATGTCGGTcctgctgat (SEQ ID NO:153) ATGGACTCTCCAGCGTtctc (SEQ ID NO:154) ATGGAAGGTCCAACGTTctc (SEQ ID NO:155) TCCATGGCGGTcctgatgct (SEQ ID NO:156) TCCATGACGGTcctgatgct (SEQ ID NO:157) TCCATGTCGATcctgatgct (SEQ ID NO:158) TCCATGTCGCTcctgatgct (SEQ ID NO:159) TCCATGTCGTTcctgatgct (SEQ ID NO:160) TCCATAACGTTcctgatgct (SEQ ID NO:161) TCCATGACGTCcctgatgct (SEQ ID NO:162) gctagaCGTTAGCGT (SEQ ID NO:163) tcaaCGTT (SEQ ID NO:164) tccatGACGTTCCTGATGCT (SEQ ID NO:165) atcgactCTCGAGCGTTCTC (SEQ ID NO:166) gcatGACGTTGAGCT (SEQ ID NO:167) tcagCGCT (SEQ ID NO:168) gagAACGGTGGACCTTCCAT (SEQ ID NO:169) gagAACGCTCGACCTTCCAT (SEQ ID NO:170) gagAACGCTCGACCTTCGAT (SEQ ID NO:171) gagAACGCTCCAGCACTGAT (SEQ ID NO:172) tccatGTCGGTCCTGATGCT (SEQ ID NO:173) tccatGTCGGTCCTGCTGAT (SEQ ID NO:174) atggactctcCAGCGTTCTC (SEQ ID NO:175) atggaaggtccAACGTTCTC (SEQ ID NO:176) tccaTGGCGGTCCTGATGCT (SEQ ID NO:177) tccatGACGGTCCTGATGCT (SEQ ID NO:178) tccatGTCGATCCTGATGCT (SEQ ID NO:179) tccatgTCGCTCCTGATGCT (SEQ ID NO:180) tccatGTCGTTCCTGATGCT (SEQ ID NO:181) tccatAACGTTCCTGATGCT (SEQ ID NO:182) tccatGACGTCCCTGATGCT (SEQ ID NO:183) gctagaCGttagcgt (SEQ ID NO:184) tcAACGtt (SEQ ID NO:185) tccatgaCGttcctgatgct (SEQ ID NO:186) atcgactctCGagcgttctc (SEQ ID NO:187) gcatgaCGttgagct (SEQ ID NO:188) tcagCGct (SEQ ID NO:189) gagaaCGctggaccttccat (SEQ ID NO:190) gagaaCGctcgaccttccat (SEQ ID NO:191) gagaaCGctCGaccttccat (SEQ ID NO:192) gagaacgctCGaccttccat (SEQ ID NO:193) gagaaCGctcgaccttcgat (SEQ ID NO:194) gagaacgctCGaccttcgat (SEQ ID NO:195) gagaaCGctCGaccttcgat (SEQ ID NO:196) gagaaCGctccagcactgat (SEQ ID NO:197) tccatgtCGgtcctgatgct (SEQ ID NO:198) tccatgtCGgtcctgctgat (SEQ ID NO:199) atggactctccagCGttctc (SEQ ID NO:200) atggaaggtccaaCGttctc (SEQ ID NO:201) tccatggCGgtcctgatgct (SEQ ID NO:202) tccatgaCGgtcctgatgct (SEQ ID NO:203) tccatgtCGatcctgatgct (SEQ ID NO:204) tccatgtCGctcctgatgct (SEQ ID NO:205) tccatgtCGttcctgatgct (SEQ ID NO:206) tccataaCGttcctgatgct (SEQ ID NO:207) tccatgaCGtccctgatgct (SEQ ID NO:208) GCTAGACGTTAGCGTttttt (SEQ ID NO:209) TCAACGTTttttt (SEQ ID NO:210) TCCATGACGTTCCTGATGCTttttt (SEQ ID NO:211) ATCGACTCTCGAGCGTTCTCttttt (SEQ ID NO:212) GCATGACGTTGAGCTttttt (SEQ ID NO:213) TCAGCGCTttttt (SEQ ID NO:214) GAGAACGCTGGACCTTCCATttttt (SEQ ID NO:215) GAGAACGCTCGACCTTCCATttttt (SEQ ID NO:216) GAGAACGCTCGAOCTTCGAtttttt (SEQ ID NO:217) GAGAACGCTCCAGCACTGAttttt (SEQ ID NO:218) TCCATGTCGGTCCTGATGCtttttttt (SEQ ID NO:219) TCCATGTCGGTCCTGCTGattttt (SEQ ID NO:220) ATGGACTCTCCAGCGTTCTCttttt (SEQ ID NO:221) ATGGAAGGTCCAACGTTCTCttttt (SEQ ID NO:222) TCCATGGCGGTCCTGATGCTttttt (SEQ ID NO:223) TCCATGACGGTCCTGATGCTttttt (SEQ ID NO:224) TCCATGTCGATCCTGATGCTttttt (SEQ ID NO:225) TCCATGTCGCTCCTGATGCTttttt (SEQ ID NO:226) TCCATGTCGTTCCTGATGCttttt (SEQ ID NO:227) TCCATAACGTTCCTGATGCttttt (SEQ ID NO:228) TCCATGACGTCCCTGATGCttttt (SEQ ID NO:229) atatatatGCTAGACGTTAGCGT (SEQ ID NO:230) atatatatCAACGTT (SEQ ID NO:231) atatatatCCATGACGTTCCTGATGCT (SEQ ID NO:232) atatatatCGACTCTCGAGCGTTCTC (SEQ ID NO:233) atatatatGCATGACGTTGAGCT (SEQ ID NO:234) atatatatCAGCGCT (SEQ ID NO:235) atatatatGAGAACGCTGGACCTTCCAT (SEQ ID NO:236) atatatatatGAGAACGCTCGACCTTCCAT (SEQ ID NO:237) atatatatGAGAACGCTCGACCTTCGAT (SEQ ID NO:238) atatatatGAGAACGCTCCAGCACTGAT (SEQ ID NO:239) atatatatTCCATGTCGGTCCTGATGCT (SEQ ID NO:240) atatatatTCCATGTCGGTCCTGCTGAT (SEQ ID NO:241) atatatatATGGACTCTCCAGCGTTCTC (SEQ ID NO:242) atatatatATGGAAGGTCCAACGTTCTC (SEQ ID NO:243) atatatatTCCATGGCGGTCCTGATGCT (SEQ ID NO:244) atatatatTCCATGACGGTCCTGATGCT (SEQ ID NO:245) atatatatTCCATGTCGATCCTGATGCT (SEQ ID NO:246) atatatatTCCATGTCGCTCCTGATGCT (SEQ ID NO:247) atatatatTCCATGTCGTTCCTGATGCT (SEQ ID NO:248) atatatatTCCATAACGTTCCTGATGCT (SEQ ID NO:249) atatatatCCATGACGTCCCTGATGCT (SEQ ID NO:250) aaaaaaaGCTAGACGTTAGCGTttttttt (SEQ ID NO:251) aaaaaaaTCAACGTTttttttt (SEQ ID NO:252) aaaaaaaTCCATGACGTTCCTGATGCTttttttt (SEQ ID NO:253) aaaaaaaATCGACTCTCGAGCGTTCTCttttttt (SEQ ID NO:254) aaaaaaaGCATGACGTTGAGCTttttttt (SEQ ID NO:255) aaaaaaaTCAGCGCTttttttt (SEQ ID NO:256) aaaaaaaGAGAACGCTGGACCTTCCATttttttt (SEQ ID NO:257) aaaaaaaGAGAACGCTCGACCTTCCATttttttt (SEQ ID NO:258) aaaaaaaGAGAACGCTCGACCTTCGATttttttt (SEQ ID NO:259) aaaaaaaGAGAACGCTCCAGCACTGATttttttt (SEQ ID NO:260) aaaaaaaTCCATGTCGGTCCTGATGCTttttttt (SEQ ID NO:261) aaaaaaaTCCATGTCGGTCCTGCTGATttttttt (SEQ ID NO:262) aaaaaaaATGGACTCTCCAGCGTTCTCttttttt (SEQ ID NO:263) aaaaaaaATGGAAGGTCCAACGTTCTGttttttt (SEQ ID NO:264) aaaaaaaTCCATGGCGGTCCTGATGCTttttttt (SEQ ID NO:265) aaaaaaaTCCATGACGGTCCTGATGCTttttttt (SEQ ID NO:266) aaaaaaaTCCATGTCGATCCTGATGCTttttttt (SEQ ID NO:267) aaaaaaaTCCATGTCGCTCCTGATGCTttttttt (SEQ ID NO:268) aaaaaaaTCCATGTCGTTCCTGATGCTttttttt (SEQ ID NO:269) aaaaaaaGCTAGACGTTAGCGttttttt (SEQ ID NO:270) aaaaaaaCAACGttttttt (SEQ ID NO:271) aaaaaaaTCCATGACGTTCCTGATGCttttttt (SEQ ID NO:272) aaaaaaaTCGACTCTCGAGCGTTCTCttttttt (SEQ ID NO:273) aaaaaaaGCATGACGTTGAGCttttttt (SEQ ID NO:274) aaaaaaaTCAGCGCttttttt (SEQ ID NO:275) aaaaaaaGAGAACGCTGGACCTTCCAttttttt (SEQ ID NO:276) aaaaaaaGAGAACGCTCGACCTTCCAttttttt (SEQ ID NO:277) aaaaaaaGAGAACGCTGGACCTTCGAttttttt (SEQ ID NO:278) aaaaaaaGAGAACGCTCCAGCACTGAttttttt (SEQ ID NO:279) aaaaaaaTCCATGTCGGTCCTGATGCttttttt (SEQ ID NO:280) aaaaaaaTCCATGTCGGTCCTGCTGAttttttt (SEQ ID NO:281) aaaaaaaTGGACTCTCCAGCGTTCTCttttttt (SEQ ID NO:282) aaaaaaaTGGAAGGTCCAACGTTCTCttttttt (SEQ ID NO:283) aaaaaaaTCCATGGCGGTCCTGATGCttttttt (SEQ ID NO:284) aaaaaaaTCCATGACGGTCCTGATGCttttttt (SEQ ID NO:285) aaaaaaaTCCATGTCGATCCTGATGCttttttt (SEQ ID NO:286) aaaaaaaTCCATGTCGCTCCTGATGCttttttt (SEQ ID NO:287) aaaaaaaTCCATGTCGTTCCTGATGCttttttt (SEQ ID NO:288) aGCTAGACGTTAGCGT (SEQ ID NO:289) aTCAACGTT (SEQ ID NO:290) aTCCATGACGTTCCTGATGCT (SEQ ID NO:291) aATCGACTCTCGAGCGTTCTC (SEQ ID NO:292) aGCATGACGTTGAGCT (SEQ ID NO:293) aTCAGCGCT (SEQ ID NO:294) aGAGAACGCTGGACCTTCCAT (SEQ ID NO:295) aGAGAACGCTCGACCTTCCAT (SEQ ID NO:296) aGAGAACGCTCGAGCTTCGAT (SEQ ID NO:297) aGAGAACGCTGCAGCACTGAT (SEQ ID NO:298) aTCCATGTCGGTCCTGATGCT (SEQ ID NO:299) aTCCATGTCGGTCCTGCTGAT (SEQ ID NO:300) aATGGACTCTCCAGCGTTCTC (SEQ ID NO:301) aATGGAAGGTOCAACGTTCTC (SEQ ID NO:302) aTCCATGGCGGTCCTGATGCT (SEQ ID NO:303) aTCCATGACGGTCCTGATGCT (SEQ ID NO:304) aTCCATGTCGATCCTGATGCT (SEQ ID NO:305) aTCCATGTCGCTCCTGATGCT (SEQ ID NO:306) aTCCATGTCGTTCCTGATGCT (SEQ ID NO:307) GCTAGACGTTAGCGTa (SEQ ID NO:308) TCAACGTTa (SEQ ID NO:309) TCCATGACGTTCCTGATGCTa (SEQ ID NO:310) ATCGACTCTCGAGCGTTCTCa (SEQ ID NO:311) GCATGACGTTGAGCTa (SEQ ID NO:312) TCAGOGOTa (SEQ ID NO:313) GAGAACGCTGGACCTTCCATa (SEQ ID NO:314) GAGAACGCTCGACCTTCCATa (SEQ ID NO:315) GAGAACGCTCGACCTTCGATa (SEQ ID NO:316) GAGAACGCTCCAGCACTGATa (SEQ ID NO:317) TCCATGTGGGTCCTGATGCTa (SEQ ID NO:318) TCCATGTCGGTCCTGCTGATa (SEQ ID NO:319) ATGGACTCTCCAGCGTTCTCa (SEQ ID NO:320) ATGGAAGGTCCAACGTTCTCa (SEQ ID NO:321) TCCATGGCGGTCCTGATGCTa (SEQ ID NO:322) TCCATGACGGTCCTGATGCTa (SEQ ID NO:323) TCCATGTCGATCCTGATGCTa (SEQ ID NO:324) TCCATGTCGCTCCTGATGCTa (SEQ ID NO:325) TCCATGTCGTTCCTGATGCTa (SEQ ID NO:326) aGCTAGACGTTAGCGTa (SEQ ID NO:327) aTCAACGTTa (SEQ ID NO:328) aTCCATGACGTTCCTGATGCTa (SEQ ID NO:329) aATCGACTCTCGAGCGTTCTCa (SEQ ID NO:330) aGCATGACGTTGAGCTa (SEQ ID NO:331) aTCAGCGCTa (SEQ ID NO:332) aGAGAACGCTGGACCTTCCATa (SEQ ID NO:333) aGAGAACGCTCGACCTTCCATa (SEQ ID NO:334) aGAGAACGCTCGACCTTCGATa (SEQ ID NO:335) aGAGAACGCTCCAGCACTGATa (SEQ ID NO:336) aTCCATGTCGGTCCTGATGCTa (SEQ ID NO:337) aTCCATGTCGGTCCTGCTGATa (SEQ ID NO:338) aATGGACTCTCCAGCGTTCTCa (SEQ ID NO:339) aATGGAAGGTCCAACGTTCTCa (SEQ ID NO:340) aTCCATGGCGGTCCTGATGCTa (SEQ ID NO:341) aTCCATGACGGTCCTGATGCTa (SEQ ID NO:342) aTCCATGTCGATCCTGATGCTa (SEQ ID NO:343) aTCCATGTCGCTCCTGATGCTa (SEQ ID NO:344) aTCCATGTCGTTCCTGATGGTa (SEQ ID NO:345) TCCATGACGTTCCTGATGCttttttttaaaaaaaa (SEQ ID NO:346) GCTAGACGTTAGCGttttttttaaaaaaaa (SEQ ID NO:347) TCAACGTTttttttaaaaaaaa (SEQ ID NO:348) TCCATGACGTTCCTGATGCTttttttttggaaaaaaaa (SEQ ID NO:349) ATCGACTCTCGAGCGTTCTCttttttttaaaaaaaa (SEQ ID NO:350) GCATGACGTTGAGCTttttttttaaaaaaaa (SEQ ID NO:351) TCAGCGCTttttttttaaaaaaaa (SEQ ID NO:352) GAGAACGCTGGACCTTCCATttttttttaaaaaaaa (SEQ ID NO:353) GAGAACGCTCGACCTTCCATttttttttaaaaaaaa (SEQ ID NO:354) GAGAACGCTCGACCTTCGATttttttttaaaaaaaa (SEQ ID NO:355) GAGAACGCTCCAGCACTGATttttttttaaaaaaaaa (SEQ ID NO:356) TCCATGTCGGTCCTGATGCTttttttttaaaaaaaaa (SEQ ID NO:357) TCCATGTCGGTCCTGCTGATttttttttaaaaaaaaa (SEQ ID NO:358) ATGGACTCTCCAGCGTTCTCttttttttaaaaaaaa (SEQ ID NO:359) ATGGAAGGTCCAAGGTTCTCttttttttaaaaaaaa (SEQ ID NO:360) TCCATGGCGGTCCTGATGCTttttttttaaaaaaaaa (SEQ ID NO:361) TCCATGACGGTCCTGATGCTttttttttaaaaaaaaa (SEQ ID NO:362) TCCATGTCGATCCTGATGCTttttttttaaaaaaaaa (SEQ ID NO:363) TGCATGTCGCTCCTGATGCTttttttttaaaaaaaaa (SEQ ID NO:364) TCCATGTCGTTCCTGATGCTttttttttaaaaaaaaa (SEQ ID NO:365) ccccccccGCTAGACGTTAGCGT (SEQ ID NO:366) ccccccccTCAACGTT (SEQ ID NO:367) ccccccccTCCATGACGTTCCTGATGCT (SEQ ID NO :368) ccccccccATCGACTCTCGAGCGTTCTC (SEQ ID NO:369) ccccccccGCATGACGTTGAGCT (SEQ ID NO:370) ccccccccTCAGCGCT (SEQ ID NO:371) ccccccccGAGAACGCTGGACCTTCCAT (SEQ ID NO:372) ccccccccGAGAACGCTCGACCTTCCAT (SEQ ID NO:373) ccccccccGAGAACGCTCGACCTTCGAT (SEQ ID NO:374) ccccccccGAGAACGCTCCAGCACTGAT (SEQ ID NO:375) ccccccccTCCATGTCGGTCCTGATGCT (SEQ ID NO:376) ccccccccTCCATGTCGGTCCTGCTGAT (SEQ ID NO:377) ccccccccATGGACTCTCCAGCGTTCTC (SEQ ID NO:378) ccccccccATGGAAGGTCCAACGTTCTC (SEQ ID NO:379) ccccccccTCCATGGCGGTCCTGATGCT (SEQ ID NO:380) ccccccccTCCATGACGGTCCTGATGCT (SEQ ID NO:381) ccccccccTCCATGTCGATCCTGATGCT (SEQ ID NO:382) ccccccccTCCATGTCGCTCCTGATGCT (SEQ ID NO:383) ccccccccTCCATGTCGTTCCTGATGCT (SEQ ID NO:384) GCTAGACGTTAGCGTgtgtgtgt (SEQ ID NO:385) TCAACGTTgtgtgtgt (SEQ ID NO:386) TCCATGACGTTCCTGATGCTgtgtgtgt (SEQ ID NO:387) ATCGACTCTCGAGCGTTCTCgtgtgtgt (SEQ ID NO:388) GCATGACGTTGAGCTgtgtgtgt (SEQ ID NO:389) TCAGCGCTgtgtgtgt (SEQ ID NO:390) GAGAACGGTGGACCTTCCATgtgtgtgt (SEQ ID NO:391) GAGAACGCTCGACCTTCCATgtgtgtgt (SEQ ID NO:392) GAGAACGCTCGACCTTCGATgtgtgtgt (SEQ ID NO:393) GAGAACGCTCCAGCACTGATgtgtgtgt (SEQ ID NO:394) TCCATGTCGGTCCTGATGCTgtgtgtgI (SEQ ID NO:395) TCCATGTCGGTCCTGCTGATgtgtgtgt (SEQ ID NO:396) ATGGACTCTCCAGCGTTCTCtgtgtgtgt (SEQ ID NO:397) ATGGAAGGTCCAACGTTCTCgtgtgtgt (SEQ ID NO:398) TCCATGGCGGTCCTGATGCTgtgtgtgt (SEQ ID NO:399) TCCATGACGGTCCTGATGCTgtgtgtgt (SEQ ID NO:400) TCCATGTCGATCCTGATGCTgtgtgtgt (SEQ ID NO:401) TCCATGTCGCTCCTGATGCTgtgtgtgt (SEQ ID NO:402) TCCATGTCGTTCCTGATGCTgtgtgtgt (SEQ ID NO:403) GCTAGACGTTAGCGt (SEQ ID NO:404) TCAACGtt (SEQ ID NO:405) TCCATGACGTTCCTGATGCt (SEQ ID NO:406) ATCGACTCTCGAGCGTTCTc (SEQ ID NO:407) GCATGACGTTGAGCt (SEQ ID NO:408) TCAGCGCt (SEQ ID NO:409) GAGAACGCTGGACCTTCCat (SEQ ID NO:410) GAGAACGCTCGACCTTCCat (SEQ ID NO:411) GAGAACGCTCGACCTTCGAt (SEQ ID NO:412) GAGAACGCTCCAGCACTGatat (SEQ ID NO:413) TCCATGTCGGTCCTGATGOt (SEQ ID NO:414) TCCATGTCGGTCCTGCTGAt (SEQ ID NO:415) ATGGACTCTCCAGCGTTCtc (SEQ ID NO:416) ATGGAAGGTCCAACGTtctc (SEQ ID NO:417) TCCATGGCGGTCCTGATGCt (SEQ ID NO:418) TCCATGACGGTCCTGATGct (SEQ ID NO:419) TCCATGTCGATCCTGATGct (SEQ ID NO:420) TCCATGTCGCTCCTGATGCt (SEQ ID NO:421) TCCATGTCGTTCCTGATGCt (SEQ ID NO:422) gCTAGACGTTAGCGt (SEQ ID NO:423) tCAACGTt (SEQ ID NO:424) tCCATGACGTTCCTGATGCt (SEQ ID NO:425) aTCGACTCTCGAGCGTTCTc (SEQ ID NO:426) gCATGACGTTGAGCt (SEQ ID NO:427) gCAGCGCt (SEQ ID NO:428) gAGAACGCTGGACCTTCCAt (SEQ ID NO:429) gAGAACGCTCGACCTTCCAt (SEQ ID NO:430) gAGAACGCTCGACCTTCGAt (SEQ ID NO:431) gAGAACGCTCCAGCACTGAt (SEQ ID NO:432) tCCATGTCGGTCCTGATGCt (SEQ ID NO:433) tCCATGTCGGTCCTGCTGAt (SEQ ID NO:434) aTGGACTCTCCAGCGTTCTc (SEQ ID NO:435) aTGGAAGGTCCAACGTTCTc (SEQ ID NO:436) tCCATGGCGGTCCTGATGCt (SEQ ID NO:437) tCCATGACGGTCCTGATGCt (SEQ iD NO:438) tCCATGTCGATCCTGATGCt (SEQ ID NO:439) tCCATGTCGCTCCTGATGCt (SEQ ID NO:440) tCCATGTCGTTCCTGATGCt (SEQ ID NO:441) GCTAGACGTTAGCGTgctagacgttagcgt (SEQ ID NO:442) TCAACGTT tccatgacgttcctgatgct (SEQ ID NO:443) TCCATGACGTTCCTGATGCTtccatgacgttcctgatgct (SEQ ID NO:444) ATCGACTCTCGAGCGTTCTCatcgactctcgagcgttctc (SEQ ID NO:445) GCATGACGTTGAGCTgcatgacgttgagct (SEQ ID NO:446) TCAGCGCTtcagcgct (SEQ ID NO:447) GAGAACGCTGGACCTTCCATgagaacgctcgaccttccat (SEQ ID NO:448) GAGAACGCTCGACCTTCCATgagaacgctcgaccttcgat (SEQ ID NO:449) GAGAACGCTCGACCTTCGATgagaacgctccagcactgat (SEQ ID NO:450) GAGAACGCTCCAGCACTGATtccatgtcggtcctgatgct (SEQ ID NO:451) TCCATGTCGGTCCTGATGGTtccatgtcggtcctgctgat (SEQ ID NO:452) TCCATGTCGGTCCTGCTGATatggactctccagcgttctc (SEQ ID NO:453) ATGGACTCTCCAGCGTTCTGatggaaggtccaacgttctc (SEQ ID NO:454) ATGGAAGGTCCAACGTTCTCtccatggcggtcctgatgct (SEQ ID NO:455) TCCATGGCGGTCCTGATGCTtccatgacggtcctgatgct (SEQ ID NO:456) TCCATGACGGTCCTGATGCTtccatgtcgatcctgatgct (SEQ ID NO:457) TCCATGTCGATCCTGATGCTtccatgtcgctcctgatgct (SEQ ID NO:458) TOCATGTCGCTCCTGATGCTtccatgtcgttcctgatgct (SEQ ID NO:459) TCCATGTCGTTCCTGATGCTtccatgacgtccctgatgct (SEQ ID NO:460) GCTAGACGTTAGCGTTTcgctaacgtctagc (SEQ ID NO:461) TCAACGTTaacgttga (SEQ ID NO:462) GGTGCATCGATGCAGGGGGGtcgagcgttctc (SEQ ID NO:463) TCCATGACGTTCCTGATGCTagcatcaggaacgtcatgga (SEQ ID NO:464) ATCGACTCTCGAGCGTTCTCgagaacgctcgagagtcgat (SEQ ID NO:465) GCATGACGTTGAGCTagctcaacgtcatgc (SEQ ID NO:466) TCAGCGCTagcgctga (SEQ ID NO:467) GAGAACGCTGGACCTTCCATatggaaggtccagcgttctc (SEQ ID NO:468) GAGAACGCTCGACCTTCCATatggaaggtcgagcgttctc (SEQ ID NO:469) GAGAACGCTCGACCTTCGATatcgaaggtcgagcgttcac (SEQ ID NO:470) GAGAACGCTCCAGCACTGATatcagtgctggagcgttcac (SEQ ID NO:471) TCCATGTCGGTCCTGATGCTaggtgcagcc (SEQ ID NO:472) TCCATGTCGGTCCTGCTGATcatgga (SEQ ID NO:473) ATGGACTCTCCAGCGTTCTCagagtccta (SEQ ID NO:474) ATGGAAGGTCCAACGTTCTCttggaccttccat (SEQ ID NO:475) TCCATGGCGGTCCTGATGCTaaaccgccatgga (SEQ ID NO:476) TCCATGACGGTCCTGATGCTtcaggaccgacat (SEQ ID NO:477) TCCATGTCGATCCTGATGCTatcgac (SEQ ID NO:478) TCCATGTCGCTCCTGATGCTcatgga (SEQ ID NO:479) TCCATGTCGTTCCTGATGCTGGAACGACATGGA (SEQ ID NO:480) CTCGAGctcgagCTCGAG (SEQ ID NO:481) ATCGAGatcgagATCGAG (SEQ ID NO:482) CTCGAGctcgagCTCGAG (SEQ ID NO:483) ATCGATatcgatATCGAT (SEQ ID NO:484) CTCGATctcgatCTCGAT (SEQ ID NO:485) atcgagCTCGAG (SEQ ID NO:486) atcgagATCGAG (SEQ ID NO:487) atcgagCTCGAG (SEQ ID NO:488) atcgatATCGAT (SEQ ID NO:489) ctcgatCTCGAT (SEQ ID NO:490) atcgagcTCGAGatcgag (SEQ ID NO:491) atcgagATCGAG atcgag (SEQ ID NO:492) atcgatCTCGAG atcgat (SEQ ID NO:493) ggtgcatcgatgcaGGGGGG (SEQ ID NO:494) ggtgcagcggtgcaGGGGGG (SEQ ID NO:495) ggtgcaccggtgcaGGGGGG (SEQ ID NO:496) ggtgtgtcgatgcaGGGGGG (SEQ ID NO:497) ggtgcatcgacgcaGGGGGG (SEQ ID NO:498) ggtgcaccgatgcaGGGGGG (SEQ ID NO:499) GGGGtgcatcgatgcaGGGGGG (SEQ ID NO:500) tgcatcgatgcaGGGGG (SEQ ID NO:501) aatgcatcgatgcaGGGGGG (SEQ ID NO:502) tgcatcgatgcaGGGGGG (SEQ ID NO:503) ggtgcaccggtgcaGGGGGG (SEQ ID NO:504) ggtgcatcgatgcaGGGGGG (SEQ ID NO:505) ggtgCAGCGGTGCAGGGGGG (SEQ ID NO:506) ggtgCACCGGTGCAGGGGGG (SEQ ID NO:507) ggtgTGTCGATGCAGGGGGG (SEQ ID NO:508) ggtgCATCGAGGCAGGGGGG (SEQ ID NO:509) ggtgCACCGATGCAGGGGGG (SEQ ID NO:510) tgcaTCGATGCAGGGGG (SEQ ID NO:511) aatgCATCGATGCAGGGGGG (SEQ ID NO:512) tgcaTCGATGCAGGGGGG (SEQ ID NO:513) ggtgCACCGGTGCAGGGGGG (SEQ ID NO:514) ggtgcatcgatgcaGGGGGGaaaaaaaa (SEQ ID NO:515) ggtgcagcggtgcaGGGGGGaaaaaaaa (SEQ ID NO:516) ggtgcaccggtgcaGGGGGGaaaaaaaa (SEQ ID NO:517) ggtgtgtcgatgcaGGGGGGaaaaaaaa (SEQ ID NO:518) ggtgcatcgacgcaGGGGGGaaaaaaaa (SEQ ID NO:519) ggtgcaccgatgcaGGGGGGaaaaaaaa (SEQ ID NO:520) GGGGtgcatcgatgcaGGGGGGaaaaaaaa (SEQ ID NO:521) tgcatcgatgcaGGGGGaaaaaaaa (SEQ ID NO:522) aatgcatcgatgcaGGGGGGaaaaaaaa (SEQ ID NO:523) tgcatcgatgcaGGGGGGaaaaaaaa (SEQ ID NO:524) ggtgcaccggtgcaGGGGGGaaaaaaaa (SEQ ID NO:525) ggggtgcatcgatgcaGGGGGGaaaaaaaa (SEQ ID NO:526) tcaacgttGGTGCATCGATGCAGGGGGG (SEQ ID NO:527) tcaacgttGGTGCAGCGGTGCAGGGGGG (SEQ ID NO:528) tcaacgttGGTGCACCGGTGCAGGGGGG (SEQ ID NO:529) tcaacgttGGTGTGTCGATGCAGGGGGG (SEQ ID NO:530) tcaacgttGGTGCATCGACGCAGGGGGG (SEQ ID NO:531) tcaacgttGGTGCACCGATGCAGGGGGG (SEQ ID NO:532) tcaacgttGGGTGCATCGATGCAGGGGGG (SEQ ID NO:533) tcaacgttTGCATCGATGCAGGGGG (SEQ ID NO:534) tcaacgttAATGCATGGATGCAGGGGGG (SEQ ID NO:535) tcaacgttTGCATCGATGCAGGGGGG (SEQ ID NO:536) tcaacgttGGTGCACCGGTGCAGGGGGG (SEQ ID NO:537) GGTGCatcgatGCAGGGGGG (SEQ ID NO:538) GGTGcagcggtcgCAGGGGGG (SEQ ID NO:539) GGTGCaccggtGCAGGGGGG (SEQ ID NO:540) GGTGTGTcgATGCAGGGGGG (SEQ ID NO:541) GGTGCatcgacGCAGGGGGG (SEQ ID NO:542) GGTGCaccgatGCAGGGGGG (SEQ ID NO:543) GGGGTGCatcgatGCAGGGGGG (SEQ ID NO:544) TGCATcgatgcaGGGGG (SEQ ID NO:545) AATGCATcgATGCAGGGGGG (SEQ ID NO:546) TGCATCGAatCAGGGGGG (SEQ ID NO:547) tatatatccccccGGTGCACCGGTGCAGGGGGGatatata (SEQ ID NO:548) tGCATCGATGCAGGGGG (SEQ ID NO:549) aatGCATCGATGCAGGGGGG (SEQ ID NO:550) tGCATCGATGCAGGGGGG (SEQ ID NO:551) atcgacTCTCGAGCGTtctc (SEQ ID NO:552) tcGAGCGTTctc (SEQ ID NO:553) tcgactCTCGAGCGttctc (SEQ ID NO:554) actCTCGAGCgttctc (SEQ ID NO:555) tctCGAGCGttctc (SEQ ID NO:556) ctcGAGCGTTct (SEQ ID NO:557) tcGAGGCttctc (SEQ ID NO:558) GCGAGGCttctc (SEQ ID NO:559) TCGATGCttctc (SEQ ID NO:560) tgcTTCGAGctc (SEQ ID NO:561) tcGTTTGTTctc (SEQ ID NO:562) TCGTATGtactc (SEQ ID NO:563) ttGTTCGTTctc (SEQ ID NO:564) ttGTTCGtactc (SEQ ID NO:565) atcgactCTCGAGCGTTCTC (SEQ ID NO:566) tcgaGCGTTCTC (SEQ ID NO:567) tcgactCTCGAGCGTTCTC (SEQ ID NO:568) actCTCGAGCGTTCTC (SEQ ID NO:569) tctCGAGCGTTCTC (SEQ ID NO:570) ctcgAGCGTTCT (SEQ ID NO:571) tcgAGGCTTCTC (SEQ ID NO:572) gcgaggCTTCTC (SEQ ID NO:573) tcgATGCTTGTC (SEQ ID NO:574) tgcTTCGAGCTC (SEQ ID NO:575) tcgtttGTTCTC (SEQ ID NO:576) tcgtatGTACTC (SEQ ID NO:577) ttgttCGTTCTC (SEQ ID NO:578) ttGTTCGTACTC (SEQ ID NO:579) atcgactctcgagcgttctcATCGACTCTCGAGCGTTCTC (SEQ ID NO:580) aaccaaccaaTCGAGCGTTCTC (SEQ ID NO:581) aaccaaccaaACTCTCGAGCGTTCTC (SEQ ID NO:582) aaccaaccaaTCTCGAGCGTTCTC (SEQ ID NO:583) aaccaaccaaCTCGAGCGTTCT (SEQ ID NO:584) aaccaaccaaTCGAGGCTTCTC (SEQ ID NO:585) aaccaaccaaGCGAGGCTTCTC (SEQ ID NO:586) aaccaaccaaTCGATGCTTCTC (SEQ ID NO:587) aaccaaccaaTGCTTCGAGCTC (SEQ ID NO:588) aaccaaccaaTCGTTTGTTCTC (SEQ ID NO:589) aaccaaccaaTCGTATGTACTC (SEQ ID NO:590) aaccaaccaaTTGTTCGTTCTC (SEQ ID NO:591) aaccaaccaaTTGTTCGTACTC (SEQ ID NO:592) aATCGACTCTCGAGCGTTCTC (SEQ ID NO:593) tCGAGCGTTCTC (SEQ ID NO:594) tCGACTCTCGAGCGTTCTC (SEQ ID NO:595) aCTCTCGAGCGTTCTC (SEQ ID NO:596) tCTCGAGCGTTCTC (SEQ ID NO:597) cTCGAGCGTTCT (SEQ ID NO:598) tCGAGGCTTCTC (SEQ ID NO:599) tCGATGCTTCTC (SEQ ID NO:600) tGCTTCGAGCTC (SEQ ID NO:601) tCGTTTGTTCTC (SEQ ID NO:602) tCGTATGTACTC (SEQ ID NO:603) tTGTTCGTTCTC (SEQ ID NO:604) tTGTTCGTACTC (SEQ ID NO:605) ATCGACTCTCGAGCGTTCTCtttttttttt (SEQ ID NO:606) TCGAGCGTTCTCtttttttttt (SEQ ID NO:607) TCGACTCTCGAGCGTTCTCtttttttttt (SEQ ID NO:608) ACTCTCGAGCGTTCTCtttttttttt (SEQ ID NO:609) TCTCGAGCGTTCTCtttttttttt (SEQ ID NO:610) CTCGAGCGTTCTtttttttttt (SEQ ID NO:611) TCGAGGCTTCTCtttttttttt (SEQ ID NO:612) GCGAGGCTTCTCtttttttttt (SEQ ID NO:613) TCGATGCTTCTCtttttttttt (SEQ ID NO:614) TGCTTCGAGCTCttttttttt (SEQ ID NO:615) TCGTTTGTTCTCtttttttttt (SEQ ID NO:616) TCGTATGTACTCtttttttttt (SEQ ID NO:617) TTGTTCGTTCTCtttttttttt (SEQ ID NO:618) TTGTTCGTACTCtttttttttt (SEQ ID NO:619) GCTAGACGTTAGCGTaacgtt (SEQ ID NO:620)

[0143] The specification is most thoroughly understood in light of the teachings of the references cited within the specification, all of which are hereby incorporated by reference in their entirety. The embodiments within the specification provide an illustration of embodiments of the invention and should not be construed to limit the scope of the invention. The skilled artisan recognizes that many other embodiments are encompassed by the claimed invention and that it is intended that the specification and examples be considered as exemplary only, with a true scope and spirit of the invention being indicated by the following claims.

0 SEQUENCE LISTING <160> NUMBER OF SEQ ID NOS: 620 <210> SEQ ID NO 1 <211> LENGTH: 30 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic oligonucleotide <400> SEQUENCE: 1 aaaaaaaaaa aaaacgttaa aaaaaaaaaa 30 <210> SEQ ID NO 2 <211> LENGTH: 30 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic DNA/RNA oligonucleotide <400> SEQUENCE: 2 aaaaaaaaaa aaaacgttaa aaaaaaaaaa 30 <210> SEQ ID NO 3 <211> LENGTH: 30 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic DNA/RNA oligonucleotide <400> SEQUENCE: 3 aaaaaaaaaa aaaacguuaa aaaaaaaaaa 30 <210> SEQ ID NO 4 <211> LENGTH: 30 <212> TYPE: RNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic RNA oligonucleotide <400> SEQUENCE: 4 aaaaaaaaaa aaaacguuaa aaaaaaaaaa 30 <210> SEQ ID NO 5 <211> LENGTH: 30 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic DNA/RNA oligonucleotide <400> SEQUENCE: 5 gggggggggg ggaacgttgg gggggggggg 30 <210> SEQ ID NO 6 <211> LENGTH: 30 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic DNA/RNA oligonucleotide <400> SEQUENCE: 6 aaaaaaaaaa aacccgggaa aaaaaaaaaa 30 <210> SEQ ID NO 7 <211> LENGTH: 30 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic DNA/RNA oligonucleotide <400> SEQUENCE: 7 aaaaaaaaaa aaaacgaaaa aaaaaaaaaa 30 <210> SEQ ID NO 8 <211> LENGTH: 30 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic DNA/RNA oligonucleotide <400> SEQUENCE: 8 gggggggggg ggaacguugg gggggggggg 30 <210> SEQ ID NO 9 <400> SEQUENCE: 9 000 <210> SEQ ID NO 10 <211> LENGTH: 30 <212> TYPE: RNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic RNA oligonucleotide <400> SEQUENCE: 10 gggggggggg ggaacguugg gggggggggg 30 <210> SEQ ID NO 11 <211> LENGTH: 30 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic oligonucleotide <400> SEQUENCE: 11 aaaaaaaaaa aaaagcttaa aaaaaaaaaa 30 <210> SEQ ID NO 12 <211> LENGTH: 14 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 12 tcaacgttaa cgtt 14 <210> SEQ ID NO 13 <211> LENGTH: 26 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 13 tccatgacgt tcctgatgct aacgtt 26 <210> SEQ ID NO 14 <211> LENGTH: 26 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 14 atcgactctc gagcgttctc aacgtt 26 <210> SEQ ID NO 15 <211> LENGTH: 21 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 15 gcatgacgtt gagctaacgt t 21 <210> SEQ ID NO 16 <211> LENGTH: 14 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 16 tcagcgctaa cgtt 14 <210> SEQ ID NO 17 <211> LENGTH: 26 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 17 gagaacgctg gaccttccat aacgtt 26 <210> SEQ ID NO 18 <211> LENGTH: 26 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 18 gagaacgctc gaccttccat aacgtt 26 <210> SEQ ID NO 19 <211> LENGTH: 26 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 19 gagaacgctc gaccttcgat aacgtt 26 <210> SEQ ID NO 20 <211> LENGTH: 26 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 20 gagaacgctc cagcactgat aacgtt 26 <210> SEQ ID NO 21 <211> LENGTH: 26 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 21 tccatgtcgg tcctgatgct aacgtt 26 <210> SEQ ID NO 22 <211> LENGTH: 26 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 22 tccatgtcgg tcctgctgat aacgtt 26 <210> SEQ ID NO 23 <211> LENGTH: 26 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 23 atggactctc cagcgttctc aacgtt 26 <210> SEQ ID NO 24 <211> LENGTH: 26 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 24 atggaaggtc caacgttctc aacgtt 26 <210> SEQ ID NO 25 <211> LENGTH: 15 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 25 gctagacgtt agcgt 15 <210> SEQ ID NO 26 <211> LENGTH: 8 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 26 tcaacgtt 8 <210> SEQ ID NO 27 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 27 tccatgacgt tcctgatgct 20 <210> SEQ ID NO 28 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 28 atcgactctc gagcgttctc 20 <210> SEQ ID NO 29 <211> LENGTH: 15 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 29 gcatgacgtt gagct 15 <210> SEQ ID NO 30 <211> LENGTH: 8 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 30 tcagcgct 8 <210> SEQ ID NO 31 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 31 gagaacgctg gaccttccat 20 <210> SEQ ID NO 32 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 32 gagaacgctc gaccttccat 20 <210> SEQ ID NO 33 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 33 gagaacgctc gaccttcgat 20 <210> SEQ ID NO 34 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 34 gagaacgctc cagcactgat 20 <210> SEQ ID NO 35 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 35 tccatgtcgg tcctgatgct 20 <210> SEQ ID NO 36 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 36 tccatgtcgg tcctgctgat 20 <210> SEQ ID NO 37 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 37 atggactctc cagcgttctc 20 <210> SEQ ID NO 38 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 38 atggaaggtc caacgttctc 20 <210> SEQ ID NO 39 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 39 tccatggcgg tcctgatgct 20 <210> SEQ ID NO 40 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 40 tccatgacgg tcctgatgct 20 <210> SEQ ID NO 41 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 41 tccatgtcga tcctgatgct 20 <210> SEQ ID NO 42 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 42 tccatgtcgc tcctgatgct 20 <210> SEQ ID NO 43 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 43 tccatgtcgt tcctgatgct 20 <210> SEQ ID NO 44 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 44 tccataacgt tcctgatgct 20 <210> SEQ ID NO 45 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 45 tccatgacgt ccctgatgct 20 <210> SEQ ID NO 46 <211> LENGTH: 26 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 46 tccatggcgg tcctgatgct aacgtt 26 <210> SEQ ID NO 47 <211> LENGTH: 26 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 47 tccatgacgg tcctgatgct aacgtt 26 <210> SEQ ID NO 48 <211> LENGTH: 26 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 48 tccatgtcga tcctgatgct aacgtt 26 <210> SEQ ID NO 49 <211> LENGTH: 26 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 49 tccatgtcgc tcctgatgct aacgtt 26 <210> SEQ ID NO 50 <211> LENGTH: 26 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 50 tccatgtcgt tcctgatgct aacgtt 26 <210> SEQ ID NO 51 <211> LENGTH: 26 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 51 tccataacgt tcctgatgct aacgtt 26 <210> SEQ ID NO 52 <211> LENGTH: 26 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 52 tccatgacgt ccctgatgct aacgtt 26 <210> SEQ ID NO 53 <211> LENGTH: 23 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 53 gctagacgtt agcgtacaac gtt 23 <210> SEQ ID NO 54 <211> LENGTH: 16 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 54 tcaacgttac aacgtt 16 <210> SEQ ID NO 55 <211> LENGTH: 28 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 55 tccatgacgt tcctgatgct acaacgtt 28 <210> SEQ ID NO 56 <211> LENGTH: 28 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 56 atcgactctc gagcgttctc acaacgtt 28 <210> SEQ ID NO 57 <211> LENGTH: 23 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 57 gcatgacgtt gagctacaac gtt 23 <210> SEQ ID NO 58 <211> LENGTH: 16 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 58 tcagcgctac aacgtt 16 <210> SEQ ID NO 59 <211> LENGTH: 28 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 59 gagaacgctg gaccttccat acaacgtt 28 <210> SEQ ID NO 60 <211> LENGTH: 28 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 60 gagaacgctc gaccttccat acaacgtt 28 <210> SEQ ID NO 61 <211> LENGTH: 28 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 61 gagaacgctc gaccttcgat acaacgtt 28 <210> SEQ ID NO 62 <211> LENGTH: 28 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 62 gagaacgctc cagcactgat acaacgtt 28 <210> SEQ ID NO 63 <211> LENGTH: 28 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 63 tccatgtcgg tcctgatgct acaacgtt 28 <210> SEQ ID NO 64 <211> LENGTH: 28 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 64 tccatgtcgg tcctgctgat acaacgtt 28 <210> SEQ ID NO 65 <211> LENGTH: 28 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 65 atggactctc cagcgttctc acaacgtt 28 <210> SEQ ID NO 66 <211> LENGTH: 28 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 66 atggaaggtc caacgttctc acaacgtt 28 <210> SEQ ID NO 67 <211> LENGTH: 28 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 67 tccatggcgg tcctgatgct acaacgtt 28 <210> SEQ ID NO 68 <211> LENGTH: 28 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 68 tccatgacgg tcctgatgct acaacgtt 28 <210> SEQ ID NO 69 <211> LENGTH: 28 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 69 tccatgtcga tcctgatgct acaacgtt 28 <210> SEQ ID NO 70 <211> LENGTH: 28 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 70 tccatgtcgc tcctgatgct acaacgtt 28 <210> SEQ ID NO 71 <211> LENGTH: 28 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 71 tccatgtcgt tcctgatgct acaacgtt 28 <210> SEQ ID NO 72 <211> LENGTH: 23 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 72 acaacgttgc tagacgttag cgt 23 <210> SEQ ID NO 73 <211> LENGTH: 16 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 73 acaacgtttc aacgtt 16 <210> SEQ ID NO 74 <211> LENGTH: 28 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 74 acaacgtttc catgacgttc ctgatgct 28 <210> SEQ ID NO 75 <211> LENGTH: 28 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 75 acaacgttat cgactctcga gcgttctc 28 <210> SEQ ID NO 76 <211> LENGTH: 23 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 76 acaacgttgc atgacgttga gct 23 <210> SEQ ID NO 77 <211> LENGTH: 16 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 77 acaacgtttc agcgct 16 <210> SEQ ID NO 78 <211> LENGTH: 28 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 78 acaacgttga gaacgctgga ccttccat 28 <210> SEQ ID NO 79 <211> LENGTH: 28 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 79 acaacgttga gaacgctcga ccttccat 28 <210> SEQ ID NO 80 <211> LENGTH: 28 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 80 acaacgttga gaacgctcga ccttcgat 28 <210> SEQ ID NO 81 <211> LENGTH: 28 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 81 acaacgttga gaacgctcca gcactgat 28 <210> SEQ ID NO 82 <211> LENGTH: 28 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 82 acaacgtttc catgtcggtc ctgatgct 28 <210> SEQ ID NO 83 <211> LENGTH: 28 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 83 acaacgtttc catgtcggtc ctgctgat 28 <210> SEQ ID NO 84 <211> LENGTH: 28 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 84 acaacgttat ggactctcca gcgttctc 28 <210> SEQ ID NO 85 <211> LENGTH: 28 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 85 acaacgttat ggaaggtcca acgttctc 28 <210> SEQ ID NO 86 <211> LENGTH: 28 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 86 acaacgtttc catggcggtc ctgatgct 28 <210> SEQ ID NO 87 <211> LENGTH: 28 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 87 acaacgtttc catgacggtc ctgatgct 28 <210> SEQ ID NO 88 <211> LENGTH: 28 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 88 acaacgtttc catgtcgatc ctgatgct 28 <210> SEQ ID NO 89 <211> LENGTH: 28 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 89 acaacgtttc catgtcgctc ctgatgct 28 <210> SEQ ID NO 90 <211> LENGTH: 28 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 90 acaacgtttc catgtcgttc ctgatgct 28 <210> SEQ ID NO 91 <211> LENGTH: 15 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 91 gctagacgtt agcgt 15 <210> SEQ ID NO 92 <211> LENGTH: 8 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 92 tcaacgtt 8 <210> SEQ ID NO 93 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 93 tccatgacgt tcctgatgct 20 <210> SEQ ID NO 94 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 94 atcgactctc gagcgttctc 20 <210> SEQ ID NO 95 <211> LENGTH: 15 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 95 gcatgacgtt gagct 15 <210> SEQ ID NO 96 <211> LENGTH: 8 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 96 tcagcgct 8 <210> SEQ ID NO 97 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 97 gagaacgctg gaccttccat 20 <210> SEQ ID NO 98 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 98 gagaacgctc gaccttccat 20 <210> SEQ ID NO 99 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 99 gagaacgctc gaccttcgat 20 <210> SEQ ID NO 100 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 100 gagaacgctc cagcactgat 20 <210> SEQ ID NO 101 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 101 tccatgtcgg tcctgatgct 20 <210> SEQ ID NO 102 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 102 tccatgtcgg tcctgctgat 20 <210> SEQ ID NO 103 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 103 atggactctc cagcgttctc 20 <210> SEQ ID NO 104 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 104 atggaaggtc caacgttctc 20 <210> SEQ ID NO 105 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 105 tccatggcgg tcctgatgct 20 <210> SEQ ID NO 106 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 106 tccatgacgg tcctgatgct 20 <210> SEQ ID NO 107 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 107 tccatgtcga tcctgatgct 20 <210> SEQ ID NO 108 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 108 tccatgtcgc tcctgatgct 20 <210> SEQ ID NO 109 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 109 tccatgtcgt tcctgatgct 20 <210> SEQ ID NO 110 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 110 tccataacgt tcctgatgct 20 <210> SEQ ID NO 111 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 111 tccatgacgt ccctgatgct 20 <210> SEQ ID NO 112 <211> LENGTH: 15 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 112 gctagacgtt agcgt 15 <210> SEQ ID NO 113 <211> LENGTH: 8 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 113 tcaacgtt 8 <210> SEQ ID NO 114 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 114 tccatgacgt tcctgatgct 20 <210> SEQ ID NO 115 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 115 atcgactctc gagcgttctc 20 <210> SEQ ID NO 116 <211> LENGTH: 15 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 116 gcatgacgtt gagct 15 <210> SEQ ID NO 117 <211> LENGTH: 8 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 117 tcagcgct 8 <210> SEQ ID NO 118 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 118 gagaacgctg gaccttccat 20 <210> SEQ ID NO 119 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 119 gagaacgctc gaccttccat 20 <210> SEQ ID NO 120 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 120 gagaacgctc gaccttcgat 20 <210> SEQ ID NO 121 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 121 gagaacgctc cagcactgat 20 <210> SEQ ID NO 122 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 122 gagaacgctc cagcactgat 20 <210> SEQ ID NO 123 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 123 gagaacgctc cagcactgat 20 <210> SEQ ID NO 124 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 124 tccatgtcgg tcctgatgct 20 <210> SEQ ID NO 125 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 125 tccatgtcgg tcctgctgat 20 <210> SEQ ID NO 126 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 126 atggactctc cagcgttctc 20 <210> SEQ ID NO 127 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 127 atggaaggtc caacgttctc 20 <210> SEQ ID NO 128 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 128 tccatggcgg tcctgatgct 20 <210> SEQ ID NO 129 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 129 tccatgacgg tcctgatgct 20 <210> SEQ ID NO 130 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 130 tccatgtcga tcctgatgct 20 <210> SEQ ID NO 131 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 131 tccatgtcgc tcctgatgct 20 <210> SEQ ID NO 132 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 132 tccatgtcgt tcctgatgct 20 <210> SEQ ID NO 133 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 133 tccataacgt tcctgatgct 20 <210> SEQ ID NO 134 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 134 tccatgacgt ccctgatgct 20 <210> SEQ ID NO 135 <211> LENGTH: 15 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 135 gctagacgtt agcgt 15 <210> SEQ ID NO 136 <211> LENGTH: 18 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 136 tcaacgtttc acgtaaaa 18 <210> SEQ ID NO 137 <211> LENGTH: 18 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 137 aaaatcaacg tttcacgt 18 <210> SEQ ID NO 138 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 138 tccatgacgt tcctgatgct 20 <210> SEQ ID NO 139 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 139 atcgactctc gagcgttctc 20 <210> SEQ ID NO 140 <211> LENGTH: 15 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 140 gcatgacgtt gagct 15 <210> SEQ ID NO 141 <211> LENGTH: 8 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 141 tcagcgct 8 <210> SEQ ID NO 142 <211> LENGTH: 8 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 142 tcagcgct 8 <210> SEQ ID NO 143 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 143 gagaacgctg gaccttccat 20 <210> SEQ ID NO 144 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 144 gagaacgctc gaccttccat 20 <210> SEQ ID NO 145 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 145 gagaacgctc gaccttcgat 20 <210> SEQ ID NO 146 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 146 gagaacgctc cagcactgat 20 <210> SEQ ID NO 147 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 147 gagaacgctc cagcactgat 20 <210> SEQ ID NO 148 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 148 gagaacgctc cagcactgat 20 <210> SEQ ID NO 149 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 149 gagaacgctc cagcactgat 20 <210> SEQ ID NO 150 <211> LENGTH: 26 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 150 gagaacgctc cagcactgat tttttt 26 <210> SEQ ID NO 151 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 151 gagaacgctc cagcactgaa aaaaa 25 <210> SEQ ID NO 152 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 152 tccatgtcgg tcctgatgct 20 <210> SEQ ID NO 153 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 153 tccatgtcgg tcctgctgat 20 <210> SEQ ID NO 154 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 154 atggactctc cagcgttctc 20 <210> SEQ ID NO 155 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 155 atggaaggtc caacgttctc 20 <210> SEQ ID NO 156 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 156 tccatggcgg tcctgatgct 20 <210> SEQ ID NO 157 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 157 tccatgacgg tcctgatgct 20 <210> SEQ ID NO 158 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 158 tccatgtcga tcctgatgct 20 <210> SEQ ID NO 159 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 159 tccatgtcgc tcctgatgct 20 <210> SEQ ID NO 160 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 160 tccatgtcgt tcctgatgct 20 <210> SEQ ID NO 161 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 161 tccataacgt tcctgatgct 20 <210> SEQ ID NO 162 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 162 tccatgacgt ccctgatgct 20 <210> SEQ ID NO 163 <211> LENGTH: 15 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 163 gctagacgtt agcgt 15 <210> SEQ ID NO 164 <211> LENGTH: 8 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 164 tcaacgtt 8 <210> SEQ ID NO 165 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 165 tccatgacgt tcctgatgct 20 <210> SEQ ID NO 166 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 166 atcgactctc gagcgttctc 20 <210> SEQ ID NO 167 <211> LENGTH: 15 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 167 gcatgacgtt gagct 15 <210> SEQ ID NO 168 <211> LENGTH: 8 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 168 tcagcgct 8 <210> SEQ ID NO 169 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 169 gagaacgctg gaccttccat 20 <210> SEQ ID NO 170 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 170 gagaacgctc gaccttccat 20 <210> SEQ ID NO 171 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 171 gagaacgctc gaccttcgat 20 <210> SEQ ID NO 172 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 172 gagaacgctc cagcactgat 20 <210> SEQ ID NO 173 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 173 tccatgtcgg tcctgatgct 20 <210> SEQ ID NO 174 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 174 tccatgtcgg tcctgctgat 20 <210> SEQ ID NO 175 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 175 atggactctc cagcgttctc 20 <210> SEQ ID NO 176 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 176 atggaaggtc caacgttctc 20 <210> SEQ ID NO 177 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 177 tccatggcgg tcctgatgct 20 <210> SEQ ID NO 178 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 178 tccatgacgg tcctgatgct 20 <210> SEQ ID NO 179 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 179 tccatgtcga tcctgatgct 20 <210> SEQ ID NO 180 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 180 tccatgtcgc tcctgatgct 20 <210> SEQ ID NO 181 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 181 tccatgtcgt tcctgatgct 20 <210> SEQ ID NO 182 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 182 tccataacgt tcctgatgct 20 <210> SEQ ID NO 183 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 183 tccatgacgt ccctgatgct 20 <210> SEQ ID NO 184 <211> LENGTH: 15 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 184 gctagacgtt agcgt 15 <210> SEQ ID NO 185 <211> LENGTH: 8 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 185 tcaacgtt 8 <210> SEQ ID NO 186 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 186 tccatgacgt tcctgatgct 20 <210> SEQ ID NO 187 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 187 atcgactctc gagcgttctc 20 <210> SEQ ID NO 188 <211> LENGTH: 15 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 188 gcatgacgtt gagct 15 <210> SEQ ID NO 189 <211> LENGTH: 8 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 189 tcagcgct 8 <210> SEQ ID NO 190 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 190 gagaacgctg gaccttccat 20 <210> SEQ ID NO 191 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 191 gagaacgctc gaccttccat 20 <210> SEQ ID NO 192 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 192 gagaacgctc gaccttccat 20 <210> SEQ ID NO 193 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 193 gagaacgctc gaccttccat 20 <210> SEQ ID NO 194 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 194 gagaacgctc gaccttcgat 20 <210> SEQ ID NO 195 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 195 gagaacgctc gaccttcgat 20 <210> SEQ ID NO 196 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 196 gagaacgctc gaccttcgat 20 <210> SEQ ID NO 197 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 197 gagaacgctc cagcactgat 20 <210> SEQ ID NO 198 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 198 tccatgtcgg tcctgatgct 20 <210> SEQ ID NO 199 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 199 tccatgtcgg tcctgctgat 20 <210> SEQ ID NO 200 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 200 atggactctc cagcgttctc 20 <210> SEQ ID NO 201 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 201 atggaaggtc caacgttctc 20 <210> SEQ ID NO 202 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 202 tccatggcgg tcctgatgct 20 <210> SEQ ID NO 203 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 203 tccatgacgg tcctgatgct 20 <210> SEQ ID NO 204 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 204 tccatgtcga tcctgatgct 20 <210> SEQ ID NO 205 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 205 tccatgtcgc tcctgatgct 20 <210> SEQ ID NO 206 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 206 tccatgtcgt tcctgatgct 20 <210> SEQ ID NO 207 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 207 tccataacgt tcctgatgct 20 <210> SEQ ID NO 208 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 208 tccatgacgt ccctgatgct 20 <210> SEQ ID NO 209 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 209 gctagacgtt agcgtttttt 20 <210> SEQ ID NO 210 <211> LENGTH: 13 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 210 tcaacgtttt ttt 13 <210> SEQ ID NO 211 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 211 tccatgacgt tcctgatgct ttttt 25 <210> SEQ ID NO 212 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 212 atcgactctc gagcgttctc ttttt 25 <210> SEQ ID NO 213 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 213 gcatgacgtt gagctttttt 20 <210> SEQ ID NO 214 <211> LENGTH: 13 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 214 tcagcgcttt ttt 13 <210> SEQ ID NO 215 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 215 gagaacgctg gaccttccat ttttt 25 <210> SEQ ID NO 216 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 216 gagaacgctc gaccttccat ttttt 25 <210> SEQ ID NO 217 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 217 gagaacgctc gaccttcgat ttttt 25 <210> SEQ ID NO 218 <211> LENGTH: 24 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 218 gagaacgctc cagcactgat tttt 24 <210> SEQ ID NO 219 <211> LENGTH: 27 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 219 tccatgtcgg tcctgatgct ttttttt 27 <210> SEQ ID NO 220 <211> LENGTH: 24 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 220 tccatgtcgg tcctgctgat tttt 24 <210> SEQ ID NO 221 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 221 atggactctc cagcgttctc ttttt 25 <210> SEQ ID NO 222 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 222 atggaaggtc caacgttctc ttttt 25 <210> SEQ ID NO 223 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 223 tccatggcgg tcctgatgct ttttt 25 <210> SEQ ID NO 224 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 224 tccatgacgg tcctgatgct ttttt 25 <210> SEQ ID NO 225 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 225 tccatgtcga tcctgatgct ttttt 25 <210> SEQ ID NO 226 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 226 tccatgtcgc tcctgatgct ttttt 25 <210> SEQ ID NO 227 <211> LENGTH: 24 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 227 tccatgtcgt tcctgatgct tttt 24 <210> SEQ ID NO 228 <211> LENGTH: 24 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 228 tccataacgt tcctgatgct tttt 24 <210> SEQ ID NO 229 <211> LENGTH: 24 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 229 tccatgacgt ccctgatgct tttt 24 <210> SEQ ID NO 230 <211> LENGTH: 23 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 230 atatatatgc tagacgttag cgt 23 <210> SEQ ID NO 231 <211> LENGTH: 15 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 231 atatatatca acgtt 15 <210> SEQ ID NO 232 <211> LENGTH: 27 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 232 atatatatcc atgacgttcc tgatgct 27 <210> SEQ ID NO 233 <211> LENGTH: 26 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 233 atatatatcg actctcgagc gttctc 26 <210> SEQ ID NO 234 <211> LENGTH: 23 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 234 atatatatgc atgacgttga gct 23 <210> SEQ ID NO 235 <211> LENGTH: 15 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 235 atatatatca gcgct 15 <210> SEQ ID NO 236 <211> LENGTH: 28 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 236 atatatatga gaacgctgga ccttccat 28 <210> SEQ ID NO 237 <211> LENGTH: 30 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 237 atatatatat gagaacgctc gaccttccat 30 <210> SEQ ID NO 238 <211> LENGTH: 28 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 238 atatatatga gaacgctcga ccttcgat 28 <210> SEQ ID NO 239 <211> LENGTH: 28 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 239 atatatatga gaacgctcca gcactgat 28 <210> SEQ ID NO 240 <211> LENGTH: 28 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 240 atatatattc catgtcggtc ctgatgct 28 <210> SEQ ID NO 241 <211> LENGTH: 28 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 241 atatatattc catgtcggtc ctgctgat 28 <210> SEQ ID NO 242 <211> LENGTH: 28 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 242 atatatatat ggactctcca gcgttctc 28 <210> SEQ ID NO 243 <211> LENGTH: 28 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 243 atatatatat ggaaggtcca acgttctc 28 <210> SEQ ID NO 244 <211> LENGTH: 28 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 244 atatatattc catggcggtc ctgatgct 28 <210> SEQ ID NO 245 <211> LENGTH: 28 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 245 atatatattc catgacggtc ctgatgct 28 <210> SEQ ID NO 246 <211> LENGTH: 28 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 246 atatatattc catgtcgatc ctgatgct 28 <210> SEQ ID NO 247 <211> LENGTH: 28 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 247 atatatattc catgtcgctc ctgatgct 28 <210> SEQ ID NO 248 <211> LENGTH: 28 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 248 atatatattc catgtcgttc ctgatgct 28 <210> SEQ ID NO 249 <211> LENGTH: 28 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 249 atatatattc cataacgttc ctgatgct 28 <210> SEQ ID NO 250 <211> LENGTH: 27 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 250 atatatatcc atgacgtccc tgatgct 27 <210> SEQ ID NO 251 <211> LENGTH: 29 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 251 aaaaaaagct agacgttagc gtttttttt 29 <210> SEQ ID NO 252 <211> LENGTH: 22 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 252 aaaaaaatca acgttttttt tt 22 <210> SEQ ID NO 253 <211> LENGTH: 34 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 253 aaaaaaatcc atgacgttcc tgatgctttt tttt 34 <210> SEQ ID NO 254 <211> LENGTH: 34 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 254 aaaaaaaatc gactctcgag cgttctcttt tttt 34 <210> SEQ ID NO 255 <211> LENGTH: 29 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 255 aaaaaaagca tgacgttgag ctttttttt 29 <210> SEQ ID NO 256 <211> LENGTH: 22 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 256 aaaaaaatca gcgctttttt tt 22 <210> SEQ ID NO 257 <211> LENGTH: 34 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 257 aaaaaaagag aacgctggac cttccatttt tttt 34 <210> SEQ ID NO 258 <211> LENGTH: 34 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 258 aaaaaaagag aacgctcgac cttccatttt tttt 34 <210> SEQ ID NO 259 <211> LENGTH: 34 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 259 aaaaaaagag aacgctcgac cttcgatttt tttt 34 <210> SEQ ID NO 260 <211> LENGTH: 34 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 260 aaaaaaagag aacgctccag cactgatttt tttt 34 <210> SEQ ID NO 261 <211> LENGTH: 34 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 261 aaaaaaatcc atgtcggtcc tgatgctttt tttt 34 <210> SEQ ID NO 262 <211> LENGTH: 34 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 262 aaaaaaatcc atgtcggtcc tgctgatttt tttt 34 <210> SEQ ID NO 263 <211> LENGTH: 34 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 263 aaaaaaaatg gactctccag cgttctcttt tttt 34 <210> SEQ ID NO 264 <211> LENGTH: 34 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 264 aaaaaaaatg gaaggtccaa cgttctcttt tttt 34 <210> SEQ ID NO 265 <211> LENGTH: 34 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 265 aaaaaaatcc atggcggtcc tgatgctttt tttt 34 <210> SEQ ID NO 266 <211> LENGTH: 34 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 266 aaaaaaatcc atgacggtcc tgatgctttt tttt 34 <210> SEQ ID NO 267 <211> LENGTH: 34 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 267 aaaaaaatcc atgtcgatcc tgatgctttt tttt 34 <210> SEQ ID NO 268 <211> LENGTH: 34 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 268 aaaaaaatcc atgtcgctcc tgatgctttt tttt 34 <210> SEQ ID NO 269 <211> LENGTH: 34 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 269 aaaaaaatcc atgtcgttcc tgatgctttt tttt 34 <210> SEQ ID NO 270 <211> LENGTH: 28 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 270 aaaaaaagct agacgttagc gttttttt 28 <210> SEQ ID NO 271 <211> LENGTH: 19 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 271 aaaaaaacaa cgttttttt 19 <210> SEQ ID NO 272 <211> LENGTH: 33 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 272 aaaaaaatcc atgacgttcc tgatgctttt ttt 33 <210> SEQ ID NO 273 <211> LENGTH: 33 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 273 aaaaaaatcg actctcgagc gttctctttt ttt 33 <210> SEQ ID NO 274 <211> LENGTH: 28 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 274 aaaaaaagca tgacgttgag cttttttt 28 <210> SEQ ID NO 275 <211> LENGTH: 21 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 275 aaaaaaatca gcgctttttt t 21 <210> SEQ ID NO 276 <211> LENGTH: 33 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 276 aaaaaaagag aacgctggac cttccatttt ttt 33 <210> SEQ ID NO 277 <211> LENGTH: 33 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 277 aaaaaaagag aacgctcgac cttccatttt ttt 33 <210> SEQ ID NO 278 <211> LENGTH: 33 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 278 aaaaaaagag aacgctcgac cttcgatttt ttt 33 <210> SEQ ID NO 279 <211> LENGTH: 33 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 279 aaaaaaagag aacgctccag cactgatttt ttt 33 <210> SEQ ID NO 280 <211> LENGTH: 33 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 280 aaaaaaatcc atgtcggtcc tgatgctttt ttt 33 <210> SEQ ID NO 281 <211> LENGTH: 33 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 281 aaaaaaatcc atgtcggtcc tgctgatttt ttt 33 <210> SEQ ID NO 282 <211> LENGTH: 33 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 282 aaaaaaatgg actctccagc gttctctttt ttt 33 <210> SEQ ID NO 283 <211> LENGTH: 33 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 283 aaaaaaatgg aaggtccaac gttctctttt ttt 33 <210> SEQ ID NO 284 <211> LENGTH: 33 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 284 aaaaaaatcc atggcggtcc tgatgctttt ttt 33 <210> SEQ ID NO 285 <211> LENGTH: 33 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 285 aaaaaaatcc atgacggtcc tgatgctttt ttt 33 <210> SEQ ID NO 286 <211> LENGTH: 33 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 286 aaaaaaatcc atgtcgatcc tgatgctttt ttt 33 <210> SEQ ID NO 287 <211> LENGTH: 33 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 287 aaaaaaatcc atgtcgctcc tgatgctttt ttt 33 <210> SEQ ID NO 288 <211> LENGTH: 33 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 288 aaaaaaatcc atgtcgttcc tgatgctttt ttt 33 <210> SEQ ID NO 289 <211> LENGTH: 16 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 289 agctagacgt tagcgt 16 <210> SEQ ID NO 290 <211> LENGTH: 9 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 290 atcaacgtt 9 <210> SEQ ID NO 291 <211> LENGTH: 21 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 291 atccatgacg ttcctgatgc t 21 <210> SEQ ID NO 292 <211> LENGTH: 21 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 292 aatcgactct cgagcgttct c 21 <210> SEQ ID NO 293 <211> LENGTH: 16 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 293 agcatgacgt tgagct 16 <210> SEQ ID NO 294 <211> LENGTH: 9 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 294 atcagcgct 9 <210> SEQ ID NO 295 <211> LENGTH: 21 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 295 agagaacgct ggaccttcca t 21 <210> SEQ ID NO 296 <211> LENGTH: 21 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 296 agagaacgct cgaccttcca t 21 <210> SEQ ID NO 297 <211> LENGTH: 21 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 297 agagaacgct cgaccttcga t 21 <210> SEQ ID NO 298 <211> LENGTH: 21 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 298 agagaacgct ccagcactga t 21 <210> SEQ ID NO 299 <211> LENGTH: 21 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 299 atccatgtcg gtcctgatgc t 21 <210> SEQ ID NO 300 <211> LENGTH: 21 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 300 atccatgtcg gtcctgctga t 21 <210> SEQ ID NO 301 <211> LENGTH: 21 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 301 aatggactct ccagcgttct c 21 <210> SEQ ID NO 302 <211> LENGTH: 21 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 302 aatggaaggt ccaacgttct c 21 <210> SEQ ID NO 303 <211> LENGTH: 21 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 303 atccatggcg gtcctgatgc t 21 <210> SEQ ID NO 304 <211> LENGTH: 21 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 304 atccatgacg gtcctgatgc t 21 <210> SEQ ID NO 305 <211> LENGTH: 21 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 305 atccatgtcg atcctgatgc t 21 <210> SEQ ID NO 306 <211> LENGTH: 21 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 306 atccatgtcg ctcctgatgc t 21 <210> SEQ ID NO 307 <211> LENGTH: 21 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 307 atccatgtcg ttcctgatgc t 21 <210> SEQ ID NO 308 <211> LENGTH: 16 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 308 gctagacgtt agcgta 16 <210> SEQ ID NO 309 <211> LENGTH: 9 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 309 tcaacgtta 9 <210> SEQ ID NO 310 <211> LENGTH: 21 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 310 tccatgacgt tcctgatgct a 21 <210> SEQ ID NO 311 <211> LENGTH: 21 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 311 atcgactctc gagcgttctc a 21 <210> SEQ ID NO 312 <211> LENGTH: 16 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 312 gcatgacgtt gagcta 16 <210> SEQ ID NO 313 <211> LENGTH: 9 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 313 tcagcgcta 9 <210> SEQ ID NO 314 <211> LENGTH: 21 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 314 gagaacgctg gaccttccat a 21 <210> SEQ ID NO 315 <211> LENGTH: 21 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 315 gagaacgctc gaccttccat a 21 <210> SEQ ID NO 316 <211> LENGTH: 21 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 316 gagaacgctc gaccttcgat a 21 <210> SEQ ID NO 317 <211> LENGTH: 21 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 317 gagaacgctc cagcactgat a 21 <210> SEQ ID NO 318 <211> LENGTH: 21 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 318 tccatgtcgg tcctgatgct a 21 <210> SEQ ID NO 319 <211> LENGTH: 21 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 319 tccatgtcgg tcctgctgat a 21 <210> SEQ ID NO 320 <211> LENGTH: 21 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 320 atggactctc cagcgttctc a 21 <210> SEQ ID NO 321 <211> LENGTH: 21 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 321 atggaaggtc caacgttctc a 21 <210> SEQ ID NO 322 <211> LENGTH: 21 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 322 tccatggcgg tcctgatgct a 21 <210> SEQ ID NO 323 <211> LENGTH: 21 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 323 tccatgacgg tcctgatgct a 21 <210> SEQ ID NO 324 <211> LENGTH: 21 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 324 tccatgtcga tcctgatgct a 21 <210> SEQ ID NO 325 <211> LENGTH: 21 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 325 tccatgtcgc tcctgatgct a 21 <210> SEQ ID NO 326 <211> LENGTH: 21 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 326 tccatgtcgt tcctgatgct a 21 <210> SEQ ID NO 327 <211> LENGTH: 17 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 327 agctagacgt tagcgta 17 <210> SEQ ID NO 328 <211> LENGTH: 10 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 328 atcaacgtta 10 <210> SEQ ID NO 329 <211> LENGTH: 22 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 329 atccatgacg ttcctgatgc ta 22 <210> SEQ ID NO 330 <211> LENGTH: 22 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 330 aatcgactct cgagcgttct ca 22 <210> SEQ ID NO 331 <211> LENGTH: 17 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 331 agcatgacgt tgagcta 17 <210> SEQ ID NO 332 <211> LENGTH: 10 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 332 atcagcgcta 10 <210> SEQ ID NO 333 <211> LENGTH: 22 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 333 agagaacgct ggaccttcca ta 22 <210> SEQ ID NO 334 <211> LENGTH: 22 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 334 agagaacgct cgaccttcca ta 22 <210> SEQ ID NO 335 <211> LENGTH: 22 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 335 agagaacgct cgaccttcga ta 22 <210> SEQ ID NO 336 <211> LENGTH: 22 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 336 agagaacgct ccagcactga ta 22 <210> SEQ ID NO 337 <211> LENGTH: 22 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 337 atccatgtcg gtcctgatgc ta 22 <210> SEQ ID NO 338 <211> LENGTH: 22 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 338 atccatgtcg gtcctgctga ta 22 <210> SEQ ID NO 339 <211> LENGTH: 22 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 339 aatggactct ccagcgttct ca 22 <210> SEQ ID NO 340 <211> LENGTH: 22 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 340 aatggaaggt ccaacgttct ca 22 <210> SEQ ID NO 341 <211> LENGTH: 22 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 341 atccatggcg gtcctgatgc ta 22 <210> SEQ ID NO 342 <211> LENGTH: 22 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 342 atccatgacg gtcctgatgc ta 22 <210> SEQ ID NO 343 <211> LENGTH: 22 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 343 atccatgtcg atcctgatgc ta 22 <210> SEQ ID NO 344 <211> LENGTH: 22 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 344 atccatgtcg ctcctgatgc ta 22 <210> SEQ ID NO 345 <211> LENGTH: 22 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 345 atccatgtcg ttcctgatgc ta 22 <210> SEQ ID NO 346 <211> LENGTH: 35 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 346 tccatgacgt tcctgatgct tttttttaaa aaaaa 35 <210> SEQ ID NO 347 <211> LENGTH: 30 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 347 gctagacgtt agcgtttttt ttaaaaaaaa 30 <210> SEQ ID NO 348 <211> LENGTH: 22 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 348 tcaacgtttt ttttaaaaaa aa 22 <210> SEQ ID NO 349 <211> LENGTH: 38 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 349 tccatgacgt tcctgatgct ttttttttgg aaaaaaaa 38 <210> SEQ ID NO 350 <211> LENGTH: 36 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 350 atcgactctc gagcgttctc ttttttttaa aaaaaa 36 <210> SEQ ID NO 351 <211> LENGTH: 31 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 351 gcatgacgtt gagctttttt tttaaaaaaa a 31 <210> SEQ ID NO 352 <211> LENGTH: 24 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 352 tcagcgcttt ttttttaaaa aaaa 24 <210> SEQ ID NO 353 <211> LENGTH: 36 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 353 gagaacgctg gaccttccat ttttttttaa aaaaaa 36 <210> SEQ ID NO 354 <211> LENGTH: 36 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 354 gagaacgctc gaccttccat ttttttttaa aaaaaa 36 <210> SEQ ID NO 355 <211> LENGTH: 36 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 355 gagaacgctc gaccttcgat ttttttttaa aaaaaa 36 <210> SEQ ID NO 356 <211> LENGTH: 37 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 356 gagaacgctc cagcactgat ttttttttaa aaaaaaa 37 <210> SEQ ID NO 357 <211> LENGTH: 37 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 357 tccatgtcgg tcctgatgct ttttttttaa aaaaaaa 37 <210> SEQ ID NO 358 <211> LENGTH: 37 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 358 tccatgtcgg tcctgctgat ttttttttaa aaaaaaa 37 <210> SEQ ID NO 359 <211> LENGTH: 36 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 359 atggactctc cagcgttctc ttttttttaa aaaaaa 36 <210> SEQ ID NO 360 <211> LENGTH: 36 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 360 atggaaggtc caacgttctc ttttttttaa aaaaaa 36 <210> SEQ ID NO 361 <211> LENGTH: 37 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 361 tccatggcgg tcctgatgct ttttttttaa aaaaaaa 37 <210> SEQ ID NO 362 <211> LENGTH: 37 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 362 tccatgacgg tcctgatgct ttttttttaa aaaaaaa 37 <210> SEQ ID NO 363 <211> LENGTH: 37 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 363 tccatgtcga tcctgatgct ttttttttaa aaaaaaa 37 <210> SEQ ID NO 364 <211> LENGTH: 37 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 364 tccatgtcgc tcctgatgct ttttttttaa aaaaaaa 37 <210> SEQ ID NO 365 <211> LENGTH: 37 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 365 tccatgtcgt tcctgatgct ttttttttaa aaaaaaa 37 <210> SEQ ID NO 366 <211> LENGTH: 23 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 366 ccccccccgc tagacgttag cgt 23 <210> SEQ ID NO 367 <211> LENGTH: 16 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 367 cccccccctc aacgtt 16 <210> SEQ ID NO 368 <211> LENGTH: 28 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 368 cccccccctc catgacgttc ctgatgct 28 <210> SEQ ID NO 369 <211> LENGTH: 28 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 369 ccccccccat cgactctcga gcgttctc 28 <210> SEQ ID NO 370 <211> LENGTH: 23 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 370 ccccccccgc atgacgttga gct 23 <210> SEQ ID NO 371 <211> LENGTH: 16 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 371 cccccccctc agcgct 16 <210> SEQ ID NO 372 <211> LENGTH: 28 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 372 ccccccccga gaacgctgga ccttccat 28 <210> SEQ ID NO 373 <211> LENGTH: 28 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 373 ccccccccga gaacgctcga ccttccat 28 <210> SEQ ID NO 374 <211> LENGTH: 28 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 374 ccccccccga gaacgctcga ccttcgat 28 <210> SEQ ID NO 375 <211> LENGTH: 28 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 375 ccccccccga gaacgctcca gcactgat 28 <210> SEQ ID NO 376 <211> LENGTH: 28 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 376 cccccccctc catgtcggtc ctgatgct 28 <210> SEQ ID NO 377 <211> LENGTH: 28 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 377 cccccccctc catgtcggtc ctgctgat 28 <210> SEQ ID NO 378 <211> LENGTH: 28 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 378 ccccccccat ggactctcca gcgttctc 28 <210> SEQ ID NO 379 <211> LENGTH: 28 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 379 ccccccccat ggaaggtcca acgttctc 28 <210> SEQ ID NO 380 <211> LENGTH: 28 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 380 cccccccctc catggcggtc ctgatgct 28 <210> SEQ ID NO 381 <211> LENGTH: 28 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 381 cccccccctc catgacggtc ctgatgct 28 <210> SEQ ID NO 382 <211> LENGTH: 28 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 382 cccccccctc catgtcgatc ctgatgct 28 <210> SEQ ID NO 383 <211> LENGTH: 28 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 383 cccccccctc catgtcgctc ctgatgct 28 <210> SEQ ID NO 384 <211> LENGTH: 28 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 384 cccccccctc catgtcgttc ctgatgct 28 <210> SEQ ID NO 385 <211> LENGTH: 23 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 385 gctagacgtt agcgtgtgtg tgt 23 <210> SEQ ID NO 386 <211> LENGTH: 16 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 386 tcaacgttgt gtgtgt 16 <210> SEQ ID NO 387 <211> LENGTH: 28 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 387 tccatgacgt tcctgatgct gtgtgtgt 28 <210> SEQ ID NO 388 <211> LENGTH: 28 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 388 atcgactctc gagcgttctc gtgtgtgt 28 <210> SEQ ID NO 389 <211> LENGTH: 23 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 389 gcatgacgtt gagctgtgtg tgt 23 <210> SEQ ID NO 390 <211> LENGTH: 16 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 390 tcagcgctgt gtgtgt 16 <210> SEQ ID NO 391 <211> LENGTH: 28 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 391 gagaacgctg gaccttccat gtgtgtgt 28 <210> SEQ ID NO 392 <211> LENGTH: 28 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 392 gagaacgctc gaccttccat gtgtgtgt 28 <210> SEQ ID NO 393 <211> LENGTH: 28 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 393 gagaacgctc gaccttcgat gtgtgtgt 28 <210> SEQ ID NO 394 <211> LENGTH: 28 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 394 gagaacgctc cagcactgat gtgtgtgt 28 <210> SEQ ID NO 395 <211> LENGTH: 28 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 395 tccatgtcgg tcctgatgct gtgtgtgt 28 <210> SEQ ID NO 396 <211> LENGTH: 28 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 396 tccatgtcgg tcctgctgat gtgtgtgt 28 <210> SEQ ID NO 397 <211> LENGTH: 29 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 397 atggactctc cagcgttctc tgtgtgtgt 29 <210> SEQ ID NO 398 <211> LENGTH: 28 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 398 atggaaggtc caacgttctc gtgtgtgt 28 <210> SEQ ID NO 399 <211> LENGTH: 28 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 399 tccatggcgg tcctgatgct gtgtgtgt 28 <210> SEQ ID NO 400 <211> LENGTH: 28 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 400 tccatgacgg tcctgatgct gtgtgtgt 28 <210> SEQ ID NO 401 <211> LENGTH: 28 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 401 tccatgtcga tcctgatgct gtgtgtgt 28 <210> SEQ ID NO 402 <211> LENGTH: 28 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 402 tccatgtcgc tcctgatgct gtgtgtgt 28 <210> SEQ ID NO 403 <211> LENGTH: 28 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 403 tccatgtcgt tcctgatgct gtgtgtgt 28 <210> SEQ ID NO 404 <211> LENGTH: 15 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 404 gctagacgtt agcgt 15 <210> SEQ ID NO 405 <211> LENGTH: 8 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 405 tcaacgtt 8 <210> SEQ ID NO 406 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 406 tccatgacgt tcctgatgct 20 <210> SEQ ID NO 407 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 407 atcgactctc gagcgttctc 20 <210> SEQ ID NO 408 <211> LENGTH: 15 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 408 gcatgacgtt gagct 15 <210> SEQ ID NO 409 <211> LENGTH: 8 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 409 tcagcgct 8 <210> SEQ ID NO 410 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 410 gagaacgctg gaccttccat 20 <210> SEQ ID NO 411 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 411 gagaacgctc gaccttccat 20 <210> SEQ ID NO 412 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 412 gagaacgctc gaccttcgat 20 <210> SEQ ID NO 413 <211> LENGTH: 22 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 413 gagaacgctc cagcactgat at 22 <210> SEQ ID NO 414 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 414 tccatgtcgg tcctgatgct 20 <210> SEQ ID NO 415 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 415 tccatgtcgg tcctgctgat 20 <210> SEQ ID NO 416 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 416 atggactctc cagcgttctc 20 <210> SEQ ID NO 417 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 417 atggaaggtc caacgttctc 20 <210> SEQ ID NO 418 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 418 tccatggcgg tcctgatgct 20 <210> SEQ ID NO 419 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 419 tccatgacgg tcctgatgct 20 <210> SEQ ID NO 420 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 420 tccatgtcga tcctgatgct 20 <210> SEQ ID NO 421 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 421 tccatgtcgc tcctgatgct 20 <210> SEQ ID NO 422 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 422 tccatgtcgt tcctgatgct 20 <210> SEQ ID NO 423 <211> LENGTH: 15 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 423 gctagacgtt agcgt 15 <210> SEQ ID NO 424 <211> LENGTH: 8 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 424 tcaacgtt 8 <210> SEQ ID NO 425 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 425 tccatgacgt tcctgatgct 20 <210> SEQ ID NO 426 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 426 atcgactctc gagcgttctc 20 <210> SEQ ID NO 427 <211> LENGTH: 15 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 427 gcatgacgtt gagct 15 <210> SEQ ID NO 428 <211> LENGTH: 8 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 428 gcagcgct 8 <210> SEQ ID NO 429 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 429 gagaacgctg gaccttccat 20 <210> SEQ ID NO 430 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 430 gagaacgctc gaccttccat 20 <210> SEQ ID NO 431 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 431 gagaacgctc gaccttcgat 20 <210> SEQ ID NO 432 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 432 gagaacgctc cagcactgat 20 <210> SEQ ID NO 433 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 433 tccatgtcgg tcctgatgct 20 <210> SEQ ID NO 434 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 434 tccatgtcgg tcctgctgat 20 <210> SEQ ID NO 435 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 435 atggactctc cagcgttctc 20 <210> SEQ ID NO 436 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 436 atggaaggtc caacgttctc 20 <210> SEQ ID NO 437 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 437 tccatggcgg tcctgatgct 20 <210> SEQ ID NO 438 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 438 tccatgacgg tcctgatgct 20 <210> SEQ ID NO 439 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 439 tccatgtcga tcctgatgct 20 <210> SEQ ID NO 440 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 440 tccatgtcgc tcctgatgct 20 <210> SEQ ID NO 441 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 441 tccatgtcgt tcctgatgct 20 <210> SEQ ID NO 442 <211> LENGTH: 30 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 442 gctagacgtt agcgtgctag acgttagcgt 30 <210> SEQ ID NO 443 <211> LENGTH: 28 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 443 tcaacgtttc catgacgttc ctgatgct 28 <210> SEQ ID NO 444 <211> LENGTH: 40 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 444 tccatgacgt tcctgatgct tccatgacgt tcctgatgct 40 <210> SEQ ID NO 445 <211> LENGTH: 40 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 445 atcgactctc gagcgttctc atcgactctc gagcgttctc 40 <210> SEQ ID NO 446 <211> LENGTH: 30 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 446 gcatgacgtt gagctgcatg acgttgagct 30 <210> SEQ ID NO 447 <211> LENGTH: 16 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 447 tcagcgcttc agcgct 16 <210> SEQ ID NO 448 <211> LENGTH: 40 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 448 gagaacgctg gaccttccat gagaacgctc gaccttccat 40 <210> SEQ ID NO 449 <211> LENGTH: 40 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 449 gagaacgctc gaccttccat gagaacgctc gaccttcgat 40 <210> SEQ ID NO 450 <211> LENGTH: 40 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 450 gagaacgctc gaccttcgat gagaacgctc cagcactgat 40 <210> SEQ ID NO 451 <211> LENGTH: 40 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 451 gagaacgctc cagcactgat tccatgtcgg tcctgatgct 40 <210> SEQ ID NO 452 <211> LENGTH: 40 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 452 tccatgtcgg tcctgatgct tccatgtcgg tcctgctgat 40 <210> SEQ ID NO 453 <211> LENGTH: 40 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 453 tccatgtcgg tcctgctgat atggactctc cagcgttctc 40 <210> SEQ ID NO 454 <211> LENGTH: 40 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 454 atggactctc cagcgttctc atggaaggtc caacgttctc 40 <210> SEQ ID NO 455 <211> LENGTH: 40 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 455 atggaaggtc caacgttctc tccatggcgg tcctgatgct 40 <210> SEQ ID NO 456 <211> LENGTH: 40 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 456 tccatggcgg tcctgatgct tccatgacgg tcctgatgct 40 <210> SEQ ID NO 457 <211> LENGTH: 40 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 457 tccatgacgg tcctgatgct tccatgtcga tcctgatgct 40 <210> SEQ ID NO 458 <211> LENGTH: 40 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 458 tccatgtcga tcctgatgct tccatgtcgc tcctgatgct 40 <210> SEQ ID NO 459 <211> LENGTH: 40 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 459 tccatgtcgc tcctgatgct tccatgtcgt tcctgatgct 40 <210> SEQ ID NO 460 <211> LENGTH: 40 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 460 tccatgtcgt tcctgatgct tccatgacgt ccctgatgct 40 <210> SEQ ID NO 461 <211> LENGTH: 31 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 461 gctagacgtt agcgtttcgc taacgtctag c 31 <210> SEQ ID NO 462 <211> LENGTH: 16 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 462 tcaacgttaa cgttga 16 <210> SEQ ID NO 463 <211> LENGTH: 32 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 463 ggtgcatcga tgcagggggg tcgagcgttc tc 32 <210> SEQ ID NO 464 <211> LENGTH: 40 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 464 tccatgacgt tcctgatgct agcatcagga acgtcatgga 40 <210> SEQ ID NO 465 <211> LENGTH: 40 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 465 atcgactctc gagcgttctc gagaacgctc gagagtcgat 40 <210> SEQ ID NO 466 <211> LENGTH: 30 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 466 gcatgacgtt gagctagctc aacgtcatgc 30 <210> SEQ ID NO 467 <211> LENGTH: 16 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 467 tcagcgctag cgctga 16 <210> SEQ ID NO 468 <211> LENGTH: 40 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 468 gagaacgctg gaccttccat atggaaggtc cagcgttctc 40 <210> SEQ ID NO 469 <211> LENGTH: 40 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 469 gagaacgctc gaccttccat atggaaggtc gagcgttctc 40 <210> SEQ ID NO 470 <211> LENGTH: 40 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 470 gagaacgctc gaccttcgat atcgaaggtc gagcgttcac 40 <210> SEQ ID NO 471 <211> LENGTH: 40 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 471 gagaacgctc cagcactgat atcagtgctg gagcgttcac 40 <210> SEQ ID NO 472 <211> LENGTH: 30 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 472 tccatgtcgg tcctgatgct aggtgcagcc 30 <210> SEQ ID NO 473 <211> LENGTH: 26 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 473 tccatgtcgg tcctgctgat catgga 26 <210> SEQ ID NO 474 <211> LENGTH: 29 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 474 atggactctc cagcgttctc agagtccta 29 <210> SEQ ID NO 475 <211> LENGTH: 33 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 475 atggaaggtc caacgttctc ttggaccttc cat 33 <210> SEQ ID NO 476 <211> LENGTH: 33 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 476 tccatggcgg tcctgatgct aaaccgccat gga 33 <210> SEQ ID NO 477 <211> LENGTH: 33 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 477 tccatgacgg tcctgatgct tcaggaccga cat 33 <210> SEQ ID NO 478 <211> LENGTH: 26 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 478 tccatgtcga tcctgatgct atcgac 26 <210> SEQ ID NO 479 <211> LENGTH: 26 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 479 tccatgtcgc tcctgatgct catgga 26 <210> SEQ ID NO 480 <211> LENGTH: 33 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 480 tccatgtcgt tcctgatgct ggaacgacat gga 33 <210> SEQ ID NO 481 <211> LENGTH: 18 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 481 ctcgagctcg agctcgag 18 <210> SEQ ID NO 482 <211> LENGTH: 18 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 482 atcgagatcg agatcgag 18 <210> SEQ ID NO 483 <211> LENGTH: 18 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 483 ctcgagctcg agctcgag 18 <210> SEQ ID NO 484 <211> LENGTH: 18 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 484 atcgatatcg atatcgat 18 <210> SEQ ID NO 485 <211> LENGTH: 18 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 485 ctcgatctcg atctcgat 18 <210> SEQ ID NO 486 <211> LENGTH: 12 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 486 atcgagctcg ag 12 <210> SEQ ID NO 487 <211> LENGTH: 12 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 487 atcgagatcg ag 12 <210> SEQ ID NO 488 <211> LENGTH: 12 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 488 atcgagctcg ag 12 <210> SEQ ID NO 489 <211> LENGTH: 12 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 489 atcgatatcg at 12 <210> SEQ ID NO 490 <211> LENGTH: 12 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 490 ctcgatctcg at 12 <210> SEQ ID NO 491 <211> LENGTH: 18 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 491 atcgagctcg agatcgag 18 <210> SEQ ID NO 492 <211> LENGTH: 18 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 492 atcgagatcg agatcgag 18 <210> SEQ ID NO 493 <211> LENGTH: 18 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 493 atcgatctcg agatcgat 18 <210> SEQ ID NO 494 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 494 ggtgcatcga tgcagggggg 20 <210> SEQ ID NO 495 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 495 ggtgcagcgg tgcagggggg 20 <210> SEQ ID NO 496 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 496 ggtgcaccgg tgcagggggg 20 <210> SEQ ID NO 497 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 497 ggtgtgtcga tgcagggggg 20 <210> SEQ ID NO 498 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 498 ggtgcatcga cgcagggggg 20 <210> SEQ ID NO 499 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 499 ggtgcaccga tgcagggggg 20 <210> SEQ ID NO 500 <211> LENGTH: 22 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 500 ggggtgcatc gatgcagggg gg 22 <210> SEQ ID NO 501 <211> LENGTH: 17 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 501 tgcatcgatg caggggg 17 <210> SEQ ID NO 502 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 502 aatgcatcga tgcagggggg 20 <210> SEQ ID NO 503 <211> LENGTH: 18 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 503 tgcatcgatg cagggggg 18 <210> SEQ ID NO 504 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 504 ggtgcaccgg tgcagggggg 20 <210> SEQ ID NO 505 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 505 ggtgcatcga tgcagggggg 20 <210> SEQ ID NO 506 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 506 ggtgcagcgg tgcagggggg 20 <210> SEQ ID NO 507 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 507 ggtgcaccgg tgcagggggg 20 <210> SEQ ID NO 508 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 508 ggtgtgtcga tgcagggggg 20 <210> SEQ ID NO 509 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 509 ggtgcatcga cgcagggggg 20 <210> SEQ ID NO 510 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 510 ggtgcaccga tgcagggggg 20 <210> SEQ ID NO 511 <211> LENGTH: 17 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 511 tgcatcgatg caggggg 17 <210> SEQ ID NO 512 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 512 aatgcatcga tgcagggggg 20 <210> SEQ ID NO 513 <211> LENGTH: 18 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 513 tgcatcgatg cagggggg 18 <210> SEQ ID NO 514 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 514 ggtgcaccgg tgcagggggg 20 <210> SEQ ID NO 515 <211> LENGTH: 28 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 515 ggtgcatcga tgcagggggg aaaaaaaa 28 <210> SEQ ID NO 516 <211> LENGTH: 28 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 516 ggtgcagcgg tgcagggggg aaaaaaaa 28 <210> SEQ ID NO 517 <211> LENGTH: 28 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 517 ggtgcaccgg tgcagggggg aaaaaaaa 28 <210> SEQ ID NO 518 <211> LENGTH: 28 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 518 ggtgtgtcga tgcagggggg aaaaaaaa 28 <210> SEQ ID NO 519 <211> LENGTH: 28 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 519 ggtgcatcga cgcagggggg aaaaaaaa 28 <210> SEQ ID NO 520 <211> LENGTH: 28 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 520 ggtgcaccga tgcagggggg aaaaaaaa 28 <210> SEQ ID NO 521 <211> LENGTH: 30 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 521 ggggtgcatc gatgcagggg ggaaaaaaaa 30 <210> SEQ ID NO 522 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 522 tgcatcgatg cagggggaaa aaaaa 25 <210> SEQ ID NO 523 <211> LENGTH: 28 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 523 aatgcatcga tgcagggggg aaaaaaaa 28 <210> SEQ ID NO 524 <211> LENGTH: 26 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 524 tgcatcgatg caggggggaa aaaaaa 26 <210> SEQ ID NO 525 <211> LENGTH: 28 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 525 ggtgcaccgg tgcagggggg aaaaaaaa 28 <210> SEQ ID NO 526 <211> LENGTH: 30 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 526 ggggtgcatc gatgcagggg ggaaaaaaaa 30 <210> SEQ ID NO 527 <211> LENGTH: 28 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 527 tcaacgttgg tgcatcgatg cagggggg 28 <210> SEQ ID NO 528 <211> LENGTH: 28 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 528 tcaacgttgg tgcagcggtg cagggggg 28 <210> SEQ ID NO 529 <211> LENGTH: 28 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 529 tcaacgttgg tgcaccggtg cagggggg 28 <210> SEQ ID NO 530 <211> LENGTH: 28 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 530 tcaacgttgg tgtgtcgatg cagggggg 28 <210> SEQ ID NO 531 <211> LENGTH: 28 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 531 tcaacgttgg tgcatcgacg cagggggg 28 <210> SEQ ID NO 532 <211> LENGTH: 28 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 532 tcaacgttgg tgcaccgatg cagggggg 28 <210> SEQ ID NO 533 <211> LENGTH: 29 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 533 tcaacgttgg gtgcatcgat gcagggggg 29 <210> SEQ ID NO 534 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 534 tcaacgtttg catcgatgca ggggg 25 <210> SEQ ID NO 535 <211> LENGTH: 28 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 535 tcaacgttaa tgcatcgatg cagggggg 28 <210> SEQ ID NO 536 <211> LENGTH: 26 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 536 tcaacgtttg catcgatgca gggggg 26 <210> SEQ ID NO 537 <211> LENGTH: 28 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 537 tcaacgttgg tgcaccggtg cagggggg 28 <210> SEQ ID NO 538 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 538 ggtgcatcga tgcagggggg 20 <210> SEQ ID NO 539 <211> LENGTH: 21 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 539 ggtgcagcgg tcgcaggggg g 21 <210> SEQ ID NO 540 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 540 ggtgcaccgg tgcagggggg 20 <210> SEQ ID NO 541 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 541 ggtgtgtcga tgcagggggg 20 <210> SEQ ID NO 542 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 542 ggtgcatcga cgcagggggg 20 <210> SEQ ID NO 543 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 543 ggtgcaccga tgcagggggg 20 <210> SEQ ID NO 544 <211> LENGTH: 22 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 544 ggggtgcatc gatgcagggg gg 22 <210> SEQ ID NO 545 <211> LENGTH: 17 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 545 tgcatcgatg caggggg 17 <210> SEQ ID NO 546 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 546 aatgcatcga tgcagggggg 20 <210> SEQ ID NO 547 <211> LENGTH: 18 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 547 tgcatcgaat cagggggg 18 <210> SEQ ID NO 548 <211> LENGTH: 40 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 548 tatatatccc cccggtgcac cggtgcaggg gggatatata 40 <210> SEQ ID NO 549 <211> LENGTH: 17 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 549 tgcatcgatg caggggg 17 <210> SEQ ID NO 550 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 550 aatgcatcga tgcagggggg 20 <210> SEQ ID NO 551 <211> LENGTH: 18 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 551 tgcatcgatg cagggggg 18 <210> SEQ ID NO 552 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 552 atcgactctc gagcgttctc 20 <210> SEQ ID NO 553 <211> LENGTH: 12 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 553 tcgagcgttc tc 12 <210> SEQ ID NO 554 <211> LENGTH: 19 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 554 tcgactctcg agcgttctc 19 <210> SEQ ID NO 555 <211> LENGTH: 16 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 555 actctcgagc gttctc 16 <210> SEQ ID NO 556 <211> LENGTH: 14 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 556 tctcgagcgt tctc 14 <210> SEQ ID NO 557 <211> LENGTH: 12 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 557 ctcgagcgtt ct 12 <210> SEQ ID NO 558 <211> LENGTH: 12 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 558 tcgaggcttc tc 12 <210> SEQ ID NO 559 <211> LENGTH: 12 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 559 gcgaggcttc tc 12 <210> SEQ ID NO 560 <211> LENGTH: 12 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 560 tcgatgcttc tc 12 <210> SEQ ID NO 561 <211> LENGTH: 12 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 561 tgcttcgagc tc 12 <210> SEQ ID NO 562 <211> LENGTH: 12 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 562 tcgtttgttc tc 12 <210> SEQ ID NO 563 <211> LENGTH: 12 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 563 tcgtatgtac tc 12 <210> SEQ ID NO 564 <211> LENGTH: 12 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 564 ttgttcgttc tc 12 <210> SEQ ID NO 565 <211> LENGTH: 12 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 565 ttgttcgtac tc 12 <210> SEQ ID NO 566 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 566 atcgactctc gagcgttctc 20 <210> SEQ ID NO 567 <211> LENGTH: 12 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 567 tcgagcgttc tc 12 <210> SEQ ID NO 568 <211> LENGTH: 19 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 568 tcgactctcg agcgttctc 19 <210> SEQ ID NO 569 <211> LENGTH: 16 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 569 actctcgagc gttctc 16 <210> SEQ ID NO 570 <211> LENGTH: 14 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 570 tctcgagcgt tctc 14 <210> SEQ ID NO 571 <211> LENGTH: 12 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 571 ctcgagcgtt ct 12 <210> SEQ ID NO 572 <211> LENGTH: 12 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 572 tcgaggcttc tc 12 <210> SEQ ID NO 573 <211> LENGTH: 12 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 573 gcgaggcttc tc 12 <210> SEQ ID NO 574 <211> LENGTH: 12 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 574 tcgatgcttc tc 12 <210> SEQ ID NO 575 <211> LENGTH: 12 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 575 tgcttcgagc tc 12 <210> SEQ ID NO 576 <211> LENGTH: 12 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 576 tcgtttgttc tc 12 <210> SEQ ID NO 577 <211> LENGTH: 12 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 577 tcgtatgtac tc 12 <210> SEQ ID NO 578 <211> LENGTH: 12 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 578 ttgttcgttc tc 12 <210> SEQ ID NO 579 <211> LENGTH: 12 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 579 ttgttcgtac tc 12 <210> SEQ ID NO 580 <211> LENGTH: 40 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 580 atcgactctc gagcgttctc atcgactctc gagcgttctc 40 <210> SEQ ID NO 581 <211> LENGTH: 22 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 581 aaccaaccaa tcgagcgttc tc 22 <210> SEQ ID NO 582 <211> LENGTH: 26 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 582 aaccaaccaa actctcgagc gttctc 26 <210> SEQ ID NO 583 <211> LENGTH: 24 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 583 aaccaaccaa tctcgagcgt tctc 24 <210> SEQ ID NO 584 <211> LENGTH: 22 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 584 aaccaaccaa ctcgagcgtt ct 22 <210> SEQ ID NO 585 <211> LENGTH: 22 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 585 aaccaaccaa tcgaggcttc tc 22 <210> SEQ ID NO 586 <211> LENGTH: 22 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 586 aaccaaccaa gcgaggcttc tc 22 <210> SEQ ID NO 587 <211> LENGTH: 22 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 587 aaccaaccaa tcgatgcttc tc 22 <210> SEQ ID NO 588 <211> LENGTH: 22 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 588 aaccaaccaa tgcttcgagc tc 22 <210> SEQ ID NO 589 <211> LENGTH: 22 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 589 aaccaaccaa tcgtttgttc tc 22 <210> SEQ ID NO 590 <211> LENGTH: 22 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 590 aaccaaccaa tcgtatgtac tc 22 <210> SEQ ID NO 591 <211> LENGTH: 22 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 591 aaccaaccaa ttgttcgttc tc 22 <210> SEQ ID NO 592 <211> LENGTH: 22 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 592 aaccaaccaa ttgttcgtac tc 22 <210> SEQ ID NO 593 <211> LENGTH: 21 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 593 aatcgactct cgagcgttct c 21 <210> SEQ ID NO 594 <211> LENGTH: 12 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 594 tcgagcgttc tc 12 <210> SEQ ID NO 595 <211> LENGTH: 19 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 595 tcgactctcg agcgttctc 19 <210> SEQ ID NO 596 <211> LENGTH: 16 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 596 actctcgagc gttctc 16 <210> SEQ ID NO 597 <211> LENGTH: 14 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 597 tctcgagcgt tctc 14 <210> SEQ ID NO 598 <211> LENGTH: 12 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 598 ctcgagcgtt ct 12 <210> SEQ ID NO 599 <211> LENGTH: 12 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 599 tcgaggcttc tc 12 <210> SEQ ID NO 600 <211> LENGTH: 12 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 600 tcgatgcttc tc 12 <210> SEQ ID NO 601 <211> LENGTH: 12 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 601 tgcttcgagc tc 12 <210> SEQ ID NO 602 <211> LENGTH: 12 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 602 tcgtttgttc tc 12 <210> SEQ ID NO 603 <211> LENGTH: 12 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 603 tcgtatgtac tc 12 <210> SEQ ID NO 604 <211> LENGTH: 12 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 604 ttgttcgttc tc 12 <210> SEQ ID NO 605 <211> LENGTH: 12 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 605 ttgttcgtac tc 12 <210> SEQ ID NO 606 <211> LENGTH: 30 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 606 atcgactctc gagcgttctc tttttttttt 30 <210> SEQ ID NO 607 <211> LENGTH: 22 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 607 tcgagcgttc tctttttttt tt 22 <210> SEQ ID NO 608 <211> LENGTH: 29 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 608 tcgactctcg agcgttctct ttttttttt 29 <210> SEQ ID NO 609 <211> LENGTH: 26 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 609 actctcgagc gttctctttt tttttt 26 <210> SEQ ID NO 610 <211> LENGTH: 24 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 610 tctcgagcgt tctctttttt tttt 24 <210> SEQ ID NO 611 <211> LENGTH: 22 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 611 ctcgagcgtt cttttttttt tt 22 <210> SEQ ID NO 612 <211> LENGTH: 22 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 612 tcgaggcttc tctttttttt tt 22 <210> SEQ ID NO 613 <211> LENGTH: 22 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 613 gcgaggcttc tctttttttt tt 22 <210> SEQ ID NO 614 <211> LENGTH: 22 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 614 tcgatgcttc tctttttttt tt 22 <210> SEQ ID NO 615 <211> LENGTH: 21 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 615 tgcttcgagc tctttttttt t 21 <210> SEQ ID NO 616 <211> LENGTH: 22 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 616 tcgtttgttc tctttttttt tt 22 <210> SEQ ID NO 617 <211> LENGTH: 22 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 617 tcgtatgtac tctttttttt tt 22 <210> SEQ ID NO 618 <211> LENGTH: 22 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 618 ttgttcgttc tctttttttt tt 22 <210> SEQ ID NO 619 <211> LENGTH: 22 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 619 ttgttcgtac tctttttttt tt 22 <210> SEQ ID NO 620 <211> LENGTH: 21 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic HDR <400> SEQUENCE: 620 gctagacgtt agcgtaacgt t 21 

We claim:
 1. An immunostimulatory composition comprising: at least one oligonucleotide comprising both an RNA region and a DNA region, wherein at least one terminus of the oligonucleotide comprises RNA.
 2. The composition of claim 1, wherein the DNA region comprises at least one unmethylated CpG dinucleotide.
 3. The composition of claim 2, wherein the DNA region comprises at least one CpG sequence.
 4. The composition of claim 2, wherein both termini comprise at least 1 RNA nucleotide.
 5. The composition of claim 3, wherein at least one terminus comprises poly A RNA.
 6. The composition of claim 1, wherein a linkage between at least two nucleotides of the oligonucleotide comprises a modification of the phosphate backbone.
 7. The composition of claim 6, wherein the modification is a phosphorathioate modification.
 8. An immunostimulatory composition comprising at least a first oligonucleotide and a second oligonucleotide, wherein both the first and second oligonucleotides each contain at least one RNA region and at least one DNA region, wherein at least one terminus of each oligonucleotide comprises RNA.
 9. The immunostimulatory composition of claim 8, wherein each oligonucleotide elicits a different immune stimulation profile.
 10. An adjuvant comprising at least one oligonucleotide comprising both an RNA region and a DNA region, wherein at least one terminus of the oligonucleotide comprises RNA.
 11. A vaccine comprising: at least one oligonucleotide comprising both an RNA region and a DNA region, wherein at least one terminus of the oligonucleotide comprises RNA, and wherein said oligonucleotide is associated with a physiological carrier or delivery system.
 12. A method of stimulating innate immunity comprising: administering at least one oligonucleotide comprising both an RNA region and a DNA region, wherein at least one terminus of the oligonucleotide comprises RNA, and wherein said oligonucleotide is associated with a physiological carrier or delivery system.
 13. A method of stimulating global immunity comprising: administering at least one oligonucleotide comprising both an RNA region and a DNA region, wherein at least one terminus of the oligonucleotide comprises RNA, and wherein said oligonucleotide is associated with a physiological carrier or delivery system.
 14. A vaccine comprising: 1) at least one oligonucleotide comprising both an RNA region and a DNA region, wherein at least one terminus of the oligonucleotide comprises RNA and, 2) at least one target antigen.
 15. A method of stimulating a cellular immune response comprising: administrating 1) at least one oligonucleotide comprising both an RNA region and a DNA region, wherein at least one terminus of the oligonucleotide comprises RNA and, 2) at least one target antigen.
 16. A method of stimulating a humoral immune response comprising: administrating 1) at least one oligonucleotide comprising both an RNA region and a DNA region, wherein at least one terminus of the oligonucleotide comprises RNA and, 2) at least one target antigen.
 17. A method of making a vaccine comprising: associating 1) at least one oligonucleotide comprising both an RNA region and a DNA region, wherein at least one terminus of the oligonucleotide comprises RNA, and 2) a physiological carrier or delivery system. 